1,6-Dihydro-1,3,5,6-Tetraaza-as-indacene based tricyclic compounds and pharmaceutical compositions comprising same

ABSTRACT

The present invention provides for tricyclic compounds having the formula (I),  
                 
 
wherein R 1 , R 2 , R 5 , R 6 , R 7 , and R 8  are as described herein. The present invention further provides pharmaceutical compositions comprising such compounds, as well as the use of such compounds for treating inflammatory and immune diseases.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/679,692, filed May 10, 2005, incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

Disclosed herein are 1,6-dihydro-1,3,5,6-tetraaza-as-indacene basedtricyclic compounds, to methods of using the compounds in treatinginflammatory and immune diseases, and cancer and to pharmaceuticalcompositions comprising same.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF-α) is a potent cytokine havingpro-inflammatory properties that is released by many cell types whenstimulated. Studies have shown a relationship between elevated levels ofTNF-α and a variety of diseases such as septic shock, hematopoiesis,tumors, and inflammatory disorders of the central nervous system,including HIV encephalitis, cerebral malaria, and meningitis.Additionally, certain neurodegenerative diseases such as Alzheimer'sdisease, Parkinson's disease, and Creutzfeldt-Jacob disease also arereportedly associated with enhanced TNF-α levels. See, e.g., Arvin etal., “The Role of Inflammation and Cytokines in Brain Injury,”Neuroscience and Biobehavioral Reviews, Vol. 20, No. 3 (1996), at pp.445-452. More recently agents which inhibit the action of TNF-α havedemonstrated clinical utility in a variety of diseases such asrheumatoid arthritis, psoriasis, and inflammatory bowel disease. See,e.g. Keating, et al. “Infliximab: An Updated Review of its use inCrohn's Disease and Rheumatoid Arthritis” BioDrugs Vol 16, (2002) pp.111-148, and Hanns-Martin, et al. “Perspectives for TNF-alpha-targetingTherapies.” Arthritis Res. Vol 4. Supp 3 (2002) pp. S 17-24.

Accordingly, various classes of drugs have been researched and developedto inhibit TNF-α production at both transcriptional and translationallevels, e.g., corticosteroids, rolipram (a phosphodiesterase IVinhibitor suppressing TNF-α mRNA synthesis), calphostin, andimidazole-type cytokine suppressing anti-inflammatory drugs (CSAIDs orP-38 inhibitors). These drugs are useful in treating a variety ofdiseases. See Dinarello, “Role of Pro- and Anti-Inflammatory CytokinesDuring Inflammation: Experimental and Clinical Findings, Review, Vol.0393-974X (1997), at pp. 91-103.

Recently, attention has focussed on the role of Nuclear factor κB(NF-κB) in the activation pathway that leads to production of TNF-α andother inflammatory cytokines and gene products. Besides TNF-α, NF-κB isinvolved in the regulation of a variety of genes involved in immunefunction and inflammation. These include the cytokines IL-1, IL-2, IL-6,IL-2Rα, and GM-GSF, the chemokines IL-8, MCP-1 (CCR2), and RANTES, theadhesion molecules, intercellular adhesion molecule-1 (ICAM-1), vascularcellular adhesion molecule-1 (VCAM-1) and E-selectin, the proteasesmatrix metalloproteinase-1 (MMP-1), MMP-9 and MMP-13, and thepro-inflammatory enzymes cyclooxygenase-2 (COX-2), iNOS, and cPLA₂.Thus, inhibition of NF-κB and/or its activation pathway provides a meansfor treating various diseases including autoimmune diseases,inflammatory diseases, Alzheimer's disease, atherosclerosis,oncogenesis, and so forth by a variety of modes of action (i.e. cytokinereduction, chemokine reduction, reduction of adhesion moleculeexpression, decreased expression of certain proteases implicated ininflammatory and immune disease processes, and decreased production ofenzymes which produce pro-inflammatory mediators) which have beenimplicated in a variety of disease progression. See, e.g., Baldwin, “TheNF-κB and IκB Proteins: New Discoveries and Insights,” Annual Rev.Immunol., Vol. 14 (1996), at pp. 649-81; see also Christman et al.,“Impact of Basic Research on Tomorrow's Medicine, The Role of NuclearFactor-κB in Pulmonary Diseases,” Chest, Vol. 117 (2000), at pp.1482-87, and Roshak, et al., “Small-molecule Inhibitors of NF-κB for theTreatment of Inflammatory Joint Disease.” Current Opinion in Pharmacol.Vol. 2 (2002) pp. 316-321.

Additionally attention has focussed on inhibition of NF-κB and/or itsactivation pathway to provide a means for treating cancer. Genes whichmediate either tumorigenesis or tumor metastasis are regulated by NF-κB.In addition NF-κB is know to be activated by carcinogens and tumorpromotors. See e.g., Karin et al.; “NF-κB in Cancer: From InnocentBystander to Major Culprit,” Nature Rev. Cancer., Vol. 2 (2002) at pp.301-310; see also Bharti et al.; “Nuclear factor-kappa B and cancer: itsrole in prevention and therapy” in Biochem. Pharmocol. at pp. 883-888.

IκB is a cytoplasmic protein that controls NF-κB activity by retainingNF-κB in the cytoplasm. IκB is phosphorylated by the IκB kinase (IKK),which has two isoforms, IKK-α (“IKK-1”) and IKK-β (“IKK-2”). When IKKphosphorylates IκB, NF-κB is rapidly released from the cytoplasm intothe cell. Upon release into the cell, NF-κB translocates to the nucleuswhere it binds to the promoters of many genes and up-regulates thetranscription of pro-inflammatory genes. Thus inhibitors of IKK-1 and/orIKK-2 would prevent translocation of NF-κB to the nucleus and preventtranscription of the pro-inflammatory gene products described above. Forexample see Burke, et al. “BMS-345541 is a Highly Selective Inhibitor ofIkB Kinase that Binds at an Allosteric Site of the Enzyme and BlocksNF-kB dependent Transcription in Mice.” J. Biol. Chem. Vol. 278, (2003)pp. 1450-1456.

The therapeutic effects of glucocorticoids are mediated in part by theirability to inhibit NF-κB activity by two mechanisms, i.e., up-regulatingIκB protein levels and inhibiting NF-κB subunits. The deleterious sideeffects of glucocorticoids (such as osteoporosis, hyperglycemia, fatredistribution, etc.) have been postulated to result from theinteraction of glucocorticoids with the glucocorticoid receptor (GR) orthe glucocorticoid response element (GRE). For example see Schacke, etal. “Mechanisms Involved in the Side Effects of Glucocorticoids”Pharmacol. and Therapeutics Vol 96 (2002) pp. 23-43. Thus inhibitors ofIKK-1 and/or IKK-2 inhibitors should provide much of the therapeuticbenefit of glucocorticoids with a greatly improved side effect profile.

As may be appreciated, those in the field of pharmaceutical researchcontinue to seek to develop new compounds and compositions havingincreased effectiveness, bioavailability, and solubility, having fewerside effects, and/or providing the physician and patient with a choiceof treatment options. Particularly in the area of immune response,individuals respond differently depending upon the type of treatment andchemical agent used. Mechanisms of action continue to be studied to aidin understanding the immune response and in developing compoundseffective for treating inflammatory and immune-related disorders.

SUMMARY OF THE INVENTION

Accordingly, presented herein are novel inhibitors of IKK enzymeactivity, or pharmaceutically acceptable salts or prodrugs thereof.

Disclosed herein are pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

Additionally, disclosed herein is a novel process and intermediates forthe preparation of the heterocyclic systems described within thisdocument.

Disclosed herein is a method for treating disorders selected fromrheumatoid arthritis, asthma, inflammaotry bowel disease, chronicobstructive pulmonary disease, psoriasis, and cancer, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

Disclosed herein is a method for treating inflammatory diseases,comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

Disclosed herein is a method for treating immunological diseases,comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

Additionally are disclosed novel compounds for use in therapy.

Additionally, disclosed herein is the use of novel compounds for themanufacture of a medicament for the treatment of inflammatory diseasesand cancer.

These and other features, which will become apparent during thefollowing detailed description, have been achieved by the inventors'discovery that compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinR¹, R², R⁵, R⁶, and R⁸ are defined below, are effective inhibitors ofIKK activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the crystal structure for Example No. A228.

DETAILED DESCRIPTION OF EMBODIMENTS

Disclosed herein are compounds of formula (I), useful in treatinginflammatory or immune conditions or cancer:

or salts thereof wherein

-   R¹ is selected from hydrogen, C₁₋₃ alkyl, C₂₋₃ alkenyl, and C₂₋₃    alkynyl;-   R² is selected from hydrogen, halo, alkyl, alkenyl, alkynyl, and    perfluoroalkyl;-   R⁵ is selected from    -   a) hydrogen and halo,    -   (b) alkyl, alkenyl, alkynyl, and haloalkyl, any of which may be        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —OR¹¹, —SR¹¹ and —NR³R⁴;-   R³ and R⁴ are independently selected from    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —OR¹¹, —NR¹²R¹³, —N(R¹²)C(O)R¹⁴, —N(R¹²)C(O)OR¹⁴,        —N(R¹²)SO₂R¹⁴, —N(R¹²)C(O)NR¹² ^(a) R¹³, —N(R¹²)SO₂NR¹² ^(a)        R¹³, —C(O)NR¹²R¹³, —SO₂R¹⁴, or —SO₂NR¹²R¹³;    -   (d) R³ and R⁴ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;-   R⁶ is    -   (a) alkyl, alkenyl, alkynyl, any of which is substituted with        one or more as valence allows Z^(1f); cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more Z¹        ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (b) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , C(O)R⁷ ^(a) ,        —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;-   R⁷ is    -   (a) hydrogen, halo, or cyano,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more Z¹        ^(c) , Z² ^(c) and Z³ ^(c) ; or-   R⁷ ^(a) is independently    -   (a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(c) , Z² ^(c) and Z³ ^(c) ;-   R⁸ is    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or-   (c) —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a)    R⁹ ^(a) ;-   R⁸ ^(a) , R⁸ ^(b) , R⁹ ^(a) and R⁹ ^(b) are independently    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ;    -   (c) R^(8a) and R^(9a) together with the nitrogen atom to which        they are attached combine to form a 3 to 8 membered heterocyclic        ring optionally independently substituted as valence allows with        one or more Z¹ ^(b) , Z² ^(b) and z³ ^(b) ; or    -   (d) R^(8b) and R^(9b) together with the nitrogen atom to which        they are attached combine to form a 3 to 8 membered heterocyclic        ring optionally independently substituted as valence allows with        one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;-   R¹⁰, at each occurance, is independently alkyl, alkenyl, alkynyl,    haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,    heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl    any of which may be optionally independently substituted as valence    allows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ;-   R¹¹, R¹², R¹² ^(a) and R¹³ are independently    -   (a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(e) , Z² ^(e) and Z³ ^(e) ;-   R¹⁴ is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,    (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which    may be optionally independently substituted as valence allows with    one or more Z¹ ^(e) , Z² ^(e) and Z³ ^(e) ;-   Z¹ ^(a-) ¹ ^(e) , Z² ^(a-) ² ^(e) , and Z³ ^(a-) ³ ^(e) are optional    substituents at each occurrence independently selected from —W¹—V¹;    —W²—V²; —W³—V³; —W⁴—V⁴; —W⁵—V⁵;-   where W¹⁻⁵ are independently    -   (1) a bond    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of        which may be optionally independently substituted as valence        allows with one or more V¹⁻⁵; or-   where V¹⁻⁵ are independently    -   (1) H    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of        which may be optionally independently substituted as valence        allows with one or more of groups (3)-(28) of V¹⁻⁵;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(O)—C(O)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)—C(O)—OY⁵,    -   (16) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (17) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (18) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (19) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (20) —U¹—C(O)—NY²Y³,    -   (21) —U¹—OC(O)—NY²Y³,    -   (22) —U¹—OC(O)—OY⁵,    -   (23) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (24) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (25) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (26) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (27) oxo;    -   (28) —U¹—Y⁵;-   Z^(1f,) at each occurrence, is independently selected from    -   (1) cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, optionally        substituted as valence allows with one or more of groups (2)        to (25) of Z^(1f);    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (24) oxo;    -   (25) —U¹—Y⁵;-   V¹ ^(a) is independently hydrogen, alkyl, —CN, —C(O)Y¹, —S(O)₂Y⁵,    —C(O)NY²Y³, S(O)₂NY²Y³;    -   Y¹, Y², Y³, Y⁴ and Y⁵    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl, any of which may be optionally independently        substituted as valence allows with one or more Z⁴, Z⁵ and z⁶; or    -   (2) Y² and Y³ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z⁴, Z⁵ and Z⁶, or    -   (4) Y² and Y³ together with the nitrogen atom to which they are        attached may combine to form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷        are each independently H or alkyl; and-   Z⁴, Z⁵, and Z⁶ are optional substituents at each occurrence    independently selected from    -   (1) H    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y^(5a),    -   (4) —U¹—S—Y^(5a),    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y^(5a) where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y^(5a),    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY² ^(a) Y³ ^(a) ,    -   (11) —U¹—N(Y⁴ ^(a) )—C(O)—Y^(1a),    -   (12) —U¹—N(Y⁴ ^(a) )—C(S)—Y^(1a),    -   (13) —U¹—N(Y⁴ ^(a) )—C(O)—NY² ^(a) Y³ ^(a) ,    -   (14) —U¹—N(Y⁴ ^(a) )—C(S)—NY² ^(a) Y³ ^(a) ,    -   (15) —U¹—N(Y⁴ ^(a) )—C(O)O—Y^(5a),    -   (16) —U¹—N(Y⁴ ^(a) )—S(O)₂—Y^(1a),    -   (17) —U¹—N(Y⁴ ^(a) )—S(O)₂—NY² ^(a) Y³ ^(a) ,    -   (18) —U¹—C(O)—NY² ^(a) Y³ ^(a) ,    -   (19) —U¹—OC(O)—NY² ^(a) Y³ ^(a) ,    -   (20) —U¹—S(O)₂—N(Y⁴ ^(a) )—Y^(1a),    -   (21) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—NY² ^(a) Y³ ^(a) ,    -   (22) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—Y^(1a),    -   (23) —U^(1—C(═NV) ¹ ^(b) )—NY² ^(a) Y^(3a),    -   (24) oxo;    -   (25) —U¹—Y^(5a);-   V^(1b) is independently hydrogen, alkyl, —CN, —C(O)Y^(1a),    —S(O)₂Y^(5a), S(O)₂NY^(2a)Y^(3a);-   Y¹ ^(a) , Y² ^(a) , Y³ ^(a) , Y⁴ ^(a) and Y^(5a)    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl;-   U¹ is independently    -   (1) a single bond,    -   (2) alkylene,    -   (3) alkenylene, or    -   (4) alkynylene.

Disclosed herein are compounds of formula (I), useful in treatinginflammatory or immune conditions or cancer:

enantiomers, diastereomers, salts, and solvates thereof wherein

-   R¹ is selected from hydrogen, C₁₋₃ alkyl, C₂₋₃ alkenyl, and C₂₋₃    alkynyl;-   R² is selected from hydrogen, alkyl, alkenyl, alkynyl, and    haloalkyl;-   R⁵ is selected from    -   a) hydrogen and halo,    -   (b) alkyl, alkenyl, alkynyl, and haloalkyl, any of which may be        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —R¹¹, —SR¹¹ and —NR³R⁴;-   R³ and R⁴ are independently selected from    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —OR¹¹, —NR¹²R¹³, —N(R¹²)C(O)R¹⁴, —N(R¹²)C(O)OR¹⁴,        —N(R¹²)SO₂R¹⁴, —N(R¹²)C(O)NR¹² ^(a) R¹³, or —N(R¹²)SO₂NR¹² ^(a)        R¹³ or —C(O)OR¹⁴, —C(O)R¹¹, —C(O)NR¹²R¹³, —SO₂R¹⁴, —SO₂NR¹²R¹³;    -   (d) R³ and R⁴ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;-   R⁶ is    -   (a) alkyl, alkenyl, alkynyl, any of which is substituted with        one or more as valence allows Z^(1f); cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more Z¹        ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (b) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , C(O)R⁷ ^(a) ,        —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;-   R⁷ is    -   (a) hydrogen, halo, or cyano,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more Z¹        ^(c) , Z² ^(c) and Z³ ^(c) ; or    -   (c) —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , —C(O)R⁷ ^(a) , —C(O)OR⁷ ^(a)        , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;-   R⁷ ^(a) and R⁷ ^(b) are independently    -   (a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(c) , Z² ^(c) and Z³ ^(c) ;-   R⁸ is    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (c) —SO₂R¹⁰, SO₂NR⁸ ^(b) R⁹ ^(b) , —C(O)R⁷ ^(a) , —C(O)OR⁷ ^(a)        , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;-   R⁸ ^(a) , R⁸ ^(b) , R⁹ ^(a) and R⁹ ^(b) are independently    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ;    -   (c) R^(8a) and R^(9a) together with the nitrogen atom to which        they are attached combine to form a 3 to 8 membered heterocyclic        ring optionally independently substituted as valence allows with        one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ; or-   (d) R^(8b) and R^(9b) together with the nitrogen atom to which they    are attached combine to form a 3 to 8 membered heterocyclic ring    optionally independently substituted as valence allows with one or    more Z¹ ^(b) , Z² ^(b) and Z³; R¹⁰, at each occurance, is    independently alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,    (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which    may be optionally independently substituted as valence allows with    one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ;-   R¹¹, R¹², R¹² ^(a) and R¹³ are independently    -   (a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(e) , Z² ^(e) and Z³ ^(e) ;-   R¹⁴ is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,    (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which    may be optionally independently substituted as valence allows with    one or more Z¹ ^(e) , Z² ^(e) and Z³ ^(e) ;-   Z¹ ^(a-) ¹ ^(e) , Z² ^(a-) ² ^(e) , and Z³ ^(a-) ³ ^(e) are optional    substituents at each occurrence independently selected from —W¹—V¹;    —W²—V²; —W³—V³; —W⁴—V⁴; —W⁵—V⁵;-   where W¹⁻⁵ are independently    -   (1) a bond    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of        which may be optionally independently substituted as valence        allows with one or more V¹⁻⁵; or-   where V¹⁻⁵ are independently    -   (1) H    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of        which may be optionally independently substituted as valence        allows with one or more of groups (3)-(25) of V¹⁻⁵;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)——Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (24) oxo;    -   (25) —U—Y⁵;-   Z^(1f,) at each occurrence, is independently selected from    -   (1) cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, optionally        substituted as valence allows with one or more of groups (2)        to (25) of Z^(1f);    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (24) oxo;    -   (25) —U¹—Y⁵;-   V^(1a) is independently hydrogen, alkyl, —CN, —C(O)Y¹, —S(O)₂Y⁵,    S(O)₂NY²Y³;-   Y¹, Y², Y³, Y⁴ and Y⁵    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl, any of which may be optionally independently        substituted as valence allows with one or more Z⁴, Z⁵ and Z⁶; or    -   (2) Y² and Y³ may together be alkylene or alkenylene, completing        a 3- to 8-membered saturated or unsaturated ring together with        the atoms to which they are attached, or    -   (4) Y² and Y³ together with the nitrogen atom to which they are        attached may combine to form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷        are each independently H or alkyl; and-   Z⁴, Z⁵, and Z⁶ are optional substituents at each occurrence    independently selected from    -   (1) H    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y^(5a),    -   (4) —U¹—S—Y^(5a),    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y^(5a) where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y^(5a,)    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY² ^(a) Y³ ^(a) ,    -   (11) —U¹—N(Y⁴ ^(a) )—C(O)—Y^(1a),    -   (12) —U¹—N(Y⁴ ^(a) )—C(S)—Y^(1a),    -   (13) —U¹—N(Y⁴ ^(a) )—C(O)—NY² ^(a) Y³ ^(a) ,    -   (14) —U¹—N(Y⁴ ^(a) )—C(S)—NY² ^(a) Y³ ^(a) ,    -   (15) —U¹—N(Y⁴ ^(a) )—C(O)O—Y^(5a),    -   (16) —U¹—N(Y⁴ ^(a) )—S(O)₂—Y^(1a),    -   (17) —U¹—N(Y⁴ ^(a) )—S(O)₂—NY² ^(a) Y³ ^(a) ,    -   (18) —U¹—C(O)—NY² ^(a) Y³ ^(a) ,    -   (19) —U¹—OC(O)—NY² ^(a) Y³ ^(a)    -   (20) —U¹—S(O)₂—N(Y⁴ ^(a) )—Y^(1a),    -   (21) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—NY² ^(a) Y³ ^(a) ,    -   (22) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—Y^(1a),    -   (23) —U¹—C(═NV¹ ^(b) )—NY² ^(a) Y^(3a),    -   (24) oxo;    -   (25) —U¹—Y^(5a);-   V^(1b) is independently hydrogen, alkyl, —CN, —C(O)Y^(1a),    —S(O)₂Y^(5a), S(O)₂NY^(2a)Y^(3a);-   Y¹ ^(a) , Y² ^(a) , Y³ ^(a) , Y⁴ ^(a) and Y^(5a)    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl;-   U¹ is independently    -   (1) a single bond,    -   (2) alkylene,    -   (3) alkenylene, or    -   (4) alkynylene.

In another embodiment are compounds of formula (I), wherein

-   R³ and R⁴ are independently    -   (a) hydrogen,    -   (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,        (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, aryl,        (aryl)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may        be optionally independently substituted as valence allows with        one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —NR¹²R¹³, C(O)OR¹⁴, or —C(O)R¹¹; or    -   (d) R³ and R⁴ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) .

In another embodiment are compounds of formula (I), wherein

-   R³ and R⁴ are independently    -   (a) hydrogen,    -   (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,        (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, aryl,        (aryl)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may        be optionally independently substituted as valence allows with        one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —NR¹²R¹³; or    -   (d) R³ and R⁴ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) .

In another embodiment are compounds of formula (I), wherein

-   R⁶ is    -   (a) alkyl, alkenyl, alkynyl, any of which is substituted with        one or more as valence allows Z^(1f); aryl, heteroaryl,        cycloalkyl, (cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl,        aryl, (aryl)alkyl, heteroaryl, or (heteroaryl)alkyl any of which        may be optionally independently substituted as valence allows        with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or-   (b) —C(O)R⁷ ^(a) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .

In another embodiment are compounds of formula (I), wherein

-   R^(7a) is independently selected from    -   (a) hydrogen, or    -   (b) alkyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,        (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or        (heteroaryl)alkyl any of which may be optionally independently        substituted as valence allows with one or more Z¹ ^(c) , Z² ^(c)        and Z³ ^(c) .

In another embodiment are compounds of formula (I), wherein

-   R³ and R⁴ are independently hydrogen, alkyl, haloalkyl,    (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl,    (aryl)alkyl or (heteroaryl)alkyl and of which may be optionally    independently substituted as valence allows with one or more Z¹ ^(b)    , Z² ^(b) and Z³ ^(b) ; —NR¹²R¹³; —C(O)OR⁴, or —C(O)R¹¹; or    alternatively, R³ and R⁴ are independently hydrogen, alkyl,    haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl,    (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which    may be optionally independently substituted as valence allows with    one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ; —NR¹²R¹³; or-   alternatively, R³ and R⁴ together with the nitrogen atom to which    they are attached combine to form a 3 to 6 membered heterocyclic    ring selected from piperidinyl, morpholinyl, pyrrolidinyl,    piperazinyl, and azetidinyl; optionally independently substituted as    valence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;-   R⁶ is    -   (a) alkyl, which is substituted with one or more as valence        allows Z^(1f); aryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl,        heterocyclo, (heterocyclo)alkyl, aryl, (aryl)alkyl, heteroaryl,        or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more Z¹        ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (b) —C(O)R⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ; or        alternatively, (b) —C(O)R⁷ ^(a) , —C(O)OR^(7a), or —C(O)NR⁸ ^(a)        R⁹ ^(a) .

In another embodiment are compounds of formula (I), wherein

-   R¹ is hydrogen, methyl, ethyl, propyl, i-propyl, prop-2-enyl,    prop-1-enyl; and-   R² is hydrogen, methyl, trifluoromethyl, and phenyl.

Compounds of formula (I), useful in treating inflammatory or immuneconditions or cancer:

enantiomers, diastereomers, salts, and solvates thereof wherein

-   R¹ is selected from hydrogen and C₁₋₃ alkyl;-   R⁶ is    -   (a) alkyl, alkenyl, alkynyl, any of which is substituted with        one or more as valence allows Z^(1f); cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more        Z^(1d), Z^(2d) and Z^(3d); or    -   (b) —C(O)R^(7a), —C(O)OR^(7a), or —C(O)NR^(8a)R^(9a);-   Z^(1a-1e), Z^(2a-2e), and Z^(3a-3e) are optional substituents at    each occurrence independently selected from —W¹—V¹; —W²—V²; —W³—V³;    —W⁴—V⁴; —W⁵—V⁵;-   where W¹⁻⁵ are independently    -   (1) a bond    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; or        where V¹⁻⁵ are independently    -   (1) H    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more of groups (3)-(25) of V¹⁻⁵;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV^(1a))—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV^(1a))—Y¹,    -   (23) —U¹—C(═NV^(1a))—NY²Y³,    -   (24) oxo;    -   (25) —U¹—Y⁵;-   Z¹ ^(f) , at each occurrence, is independently selected from    -   (1) cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, optionally        substituted as valence allows with groups (2) to (25);    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (24) oxo;    -   (25) —U¹—Y⁵;-   V^(1a) is independently hydrogen, alkyl, —CN, —C(O)Y¹, —S(O)₂Y⁵,    S(O)₂NY²Y³;-   Y¹, Y², Y³, Y⁴ and Y⁵    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl, any of which may be optionally independently        substituted as valence allows with one or more Z⁴, Z⁵ and Z⁶; or    -   (2) Y² and Y³ may together be alkylene or alkenylene, completing        a 3- to 8-membered saturated or unsaturated ring together with        the atoms to which they are attached, or    -   (4) Y² and Y³ together with the nitrogen atom to which they are        attached may combine to form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷        are each independently H or alkyl.

In another embodiment are compounds of formula (I) wherein

-   R¹ is selected from hydrogen and C₁₋₃ alkyl;-   R⁶ is    -   (a) alkyl, alkenyl, alkynyl, any of which is substituted with        one or more as valence allows Z^(1f); cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more        Z^(1d), Z^(2d) and Z^(3d); or    -   (b) —C(O)R^(7a), —C(O)OR^(7a), or —C(O)NR^(8a)R^(9a);-   Z^(1a-1e), Z^(2a-2e), and Z^(3a-3e) are optional substituents at    each occurrence independently selected from —W¹—V¹; —W²—V²; —W³—V³;    —W⁴—V⁴; —W⁵—V⁵;-   where W¹⁻⁵ are independently    -   (1) a bond    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; or        where V¹⁻⁵ are independently    -   (1) H    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more of groups (3)-(28) of V¹⁻⁵;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(O)—C(O)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)—C(O)—OY⁵,    -   (16) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (17) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (18) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (19) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (20) —U¹—C(O)—NY²Y³,    -   (21) —U¹—OC(O)—NY²Y³,    -   (22) —U¹—OC(O)—OY⁵,    -   (23) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (24) —U¹—N(Y⁴)—C(═NV^(1a))—NY²Y³,    -   (25) —U¹—N(Y⁴)—C(═NV^(1a))—Y¹,    -   (26) —U¹—C(═NV^(1a))—NY²Y³,    -   (27) oxo;    -   (2528 —U¹—Y⁵;-   Z¹ ^(f) , at each occurrence, is independently selected from    -   (1) cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, optionally        substituted as valence allows with groups (2) to (25);    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (24) oxo;    -   (25) —U¹—Y⁵;-   V^(1a) is independently hydrogen, alkyl, —CN, —C(O)Y¹, —C(O)NY²Y³,    —S(O)₂Y⁵, S(O)₂NY²Y³;-   Y¹, Y², Y³, Y⁴ and Y⁵    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl, any of which may be optionally independently        substituted as valence allows with one or more Z⁴, Z⁵ and Z⁶; or    -   (2) Y² and Y³ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z⁴, Z⁵ and Z⁶, or    -   (4) Y² and Y³ together with the nitrogen atom to which they are        attached may combine to form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷        are each independently H or alkyl.

In another embodiment are compounds of formula (I) wherein

-   R³ and R⁴ are independently    -   (a) hydrogen,    -   (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,        (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or        (heteroaryl)alkyl any of which may be optionally independently        substituted as valence allows with one or more Z^(1b), Z^(2b)        and Z^(3b);    -   (c) —NR¹²R¹³; or    -   (d) R³ and R⁴ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z^(1b), Z^(2b) and Z^(3b).

In another embodiment are compounds of formula (I) wherein

-   R⁶ is    -   (a) alkyl, alkenyl, alkynyl any of which is substituted with one        or more as valence allows Z^(1f); aryl, heteroaryl,        (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or        (heteroaryl)alkyl any of which may be optionally independently        substituted as valence allows with one or more Z^(1d), Z^(2d)        and Z^(3d); or    -   (b) —C(O)R^(7a), —C(O)OR^(7a), or —C(O)NR^(8a)R^(9a).

In another embodiment are compounds of formula (I) wherein

-   R^(7a) is independently selected from    -   (a) hydrogen, or    -   (b) alkyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,        (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or        (heteroaryl)alkyl any of which may be optionally independently        substituted as valence allows with one or more Z^(1c), Z^(2c)        and Z^(3c).

In another embodiment are compounds of formula (I) wherein

-   Z^(1b), Z^(2b) and Z^(3b) are optional substituents independently    selected from alkyl, heteroaryl, —OH, —O—Y⁵, —U¹—NY²Y³, —C(O)_(t)H,    —C(O)_(t)Y⁵;-   Z^(1c) is    -   (a) —OH, —OY⁵ or    -   (b) aryl optionally substituted with —OH or —OY⁵;-   Z^(1d), Z^(2d) and Z^(3d) are optional substituents independently    selected from    -   (a) cyano, halo, —OH, —OY⁵, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y,        —S(O)_(t)Y⁵;        -   (b) alkyl or alkoxy optionally substituted with one or more            cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y,            —U¹—N(Y⁴)—C(O)—Y¹, —U¹—N(Y⁴)—C(O)—NY²Y³, —U¹—N(Y⁴)—C(O)O—Y⁵,            —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,            —S(O)_(t)Y, —U¹-heteroaryl.

In another embodiment are compounds of formula (I) wherein

-   Z^(1b), Z^(2b) and Z^(3b) are optional substituents independently    selected from alkyl, heteroaryl, —OH, —O—Y⁵, —U¹—NY²Y³, —C(O)_(t)H,    —C(O)_(t)Y⁵;-   Z^(1c) is    -   (a) —OH, —OY⁵ or    -   (b) aryl optionally substituted with —OH or —OY⁵;-   Z^(1d), Z^(2d) and Z^(3d) are optional substituents independently    selected from    -   (a) cyano, halo, —OH, —OY⁵, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y¹,        —U¹—C(O)—NY²Y³, —S(O)_(t)Y⁵;        -   (b) alkyl or alkoxy optionally substituted with one or more            cyano, halo, —OH, —OY⁵, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y¹,            —U¹—C(O)—NY²Y³, —OC(O)—NY²Y³, OC(O)—OY⁵, —U¹—N(Y⁴)—C(O)—Y¹,            —U¹—N(Y⁴)—C(O)—NY²Y³, —U¹—N(Y⁴)—C(O)O—Y⁵, —N(Y⁴)—S(O)₂—Y¹,            —N(Y⁴)—C(O)—C(O)—NY²Y³, —N(Y⁴)—C(O)—C(O)—OY⁵,            —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,            —S(O)_(t)Y, —U¹-heteroaryl, or U1-heterocyclo, wherein            heteroaryl and heterocyclo are substituted as valence allows            with one or more of groups (3)-(28) of V¹⁻⁵.

In another embodiment are compounds of formula (I) wherein

-   R³ is hydrogen;-   R⁴ is alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,    (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or    (heteroaryl)alkyl and of which may be optionally independently    substituted as valence allows with one or more Z^(1b), Z^(2b) and    Z^(3b);-   alternatively, R³ and R⁴ together with the nitrogen atom to which    they are attached combine to form a 3 to 6 membered heterocyclic    ring selected from piperidinyl, morpholinyl, pyrrolidinyl, and    azetidinyl; optionally independently substituted as valence allows    with one or more Z^(1b), Z^(2b) and Z^(3b);-   R⁶ is    -   (a) alkynyl optionally substituted with Z^(1d) where Z^(1d) is        aryl which may be further optionally independently substituted        with one or more cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,        —C(O)_(t)Y, or, —S(O)_(t)Y; or    -   (b) aryl optionally independently substituted as valence allows        with one or more Z^(1d), Z^(2d) and Z^(3d);    -   (c) heteroaryl optionally independently substituted as valence        allows with one or more Z^(1d), Z^(2d) and Z^(3d); or    -   (d) —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;-   where U¹ is a bond or alkylene.

In another embodiment are compounds of formula (I) wherein

-   R³ is hydrogen;-   R⁴ is alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,    (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or    (heteroaryl)alkyl and of which may be optionally independently    substituted as valence allows with one or more Z^(1b), Z^(2b) and    Z^(3b);-   alternatively, R³ and R⁴ together with the nitrogen atom to which    they are attached combine to form a 3 to 6 membered heterocyclic    ring selected from piperidinyl, morpholinyl, pyrrolidinyl, and    azetidinyl; optionally independently substituted as valence allows    with one or more Z^(1b), Z^(2b) and Z^(3b);-   R⁶ is    -   (a) alkynyl optionally substituted with Z^(1d) where Z^(1d) is        aryl which may be further optionally independently substituted        with one or more cyano, halo, —OH, —OY, —U¹—NY²—Y³, —C(O)_(t)H,        —C(O)_(t)Y, or, —S(O)_(t)Y; or    -   (b) aryl optionally independently substituted as valence allows        with one or more Z^(1d), Z^(2d) and Z^(3d);-   where U¹ is a bond or alkylene;-   Z^(1c) is    -   (a) —OY where Y is aryl, or    -   (b) aryl optionally substituted with —OH or —OY where Y is        alkyl;-   Z^(1d), Z^(2d) and Z^(3d) are optional substituents independently    selected from    -   (a) cyano, halo, —OH, —OY, —C(O)_(t)H, —C(O)_(t)Y, —S(O)_(t)Y,        or        -   (b) alkyl or alkoxy optionally substituted with one or more            cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y,            —U¹—N(Y⁴)—C(O)—Y¹, —U¹—N(Y⁴)—C(O)—NY²Y³, —U¹—N(Y⁴)—C(O)O—Y⁵,            —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,            —S(O)_(t)Y, —U¹-heteroaryl;            -   where                -   U¹ is a bond or alkylene.

In another embodiment are compounds of formula (I) wherein

-   R¹ is alkyl; and-   R² is hydrogen.

In another embodiment are compounds of formula (I) wherein

-   R⁵ is selected from    -   a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, and haloalkyl, any of which may be        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   R⁶ is    -    which may be further substituted with with one or more Z¹ ^(d)        , Z² ^(d) and Z³ ^(d) .

In another embodiment are compounds of formula (I) wherein

enantiomers, diastereomers, salts, and solvates thereof wherein

-   R¹ is selected from hydrogen, C₁₋₃ alkyl, C₂₋₃ alkenyl, and C₂₋₃    alkynyl;-   R² is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,-   R⁵ is selected from    -   a) hydrogen and halo,    -   (b) alkyl, alkenyl, alkynyl, and haloalkyl, any of which may be        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —OR¹¹, —SR¹¹ and —NR³R⁴;-   R³ and R⁴ are independently selected from    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   (c) —OR¹¹, —NR¹²R¹³, —N(R¹²)C(O)R¹⁴, —N(R¹²)C(O)OR¹⁴,        —N(R¹²)SO₂R¹⁴, —N(R¹²)C(O)NR¹² ^(a) R¹³, or —N(R¹²)SO₂NR¹² ^(a)        R¹³ or —C(O)OR¹⁴, —C(O)R¹¹, —C(O)NR¹²R¹³, —SO₂R¹⁴, —SO₂NR¹²R¹³;    -   (d) R³ and R⁴ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;-   R⁶ is    -   (a) alkyl, alkenyl, alkynyl, any of which is substituted with        one or more as valence allows Z^(1f); cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more Z¹        ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   b) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , C(O)R⁷ ^(a) ,        —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;-   R⁷ is    -   (a) hydrogen, hydroxy, halo, or cyano,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclo,        aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,        (aryl)alkyl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more Z¹        ^(c) , Z² ^(c) and Z³ ^(c) ; or    -   (c) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , —C(O)R⁷ ^(a) ,        —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;-   R⁷ ^(a) and R⁷ ^(b) are independently    -   (a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(c) , Z² ^(c) and Z³ ^(c) ;-   R⁸ ^(a) , R⁸ ^(b) , R⁹ ^(a) and R⁹ ^(b) are independently    -   (a) hydrogen,    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ;    -   (c) R^(8a) and R^(9a) together with the nitrogen atom to which        they are attached combine to form a 3 to 8 membered heterocyclic        ring optionally independently substituted as valence allows with        one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ; or    -   (d) R^(8b) and R^(9b) together with the nitrogen atom to which        they are attached combine to form a 3 to 8 membered heterocyclic        ring optionally independently substituted as valence allows with        one or more Z¹ ^(b) , Z² ^(b) and Z³;-   R¹⁰, at each occurance, is independently alkyl, alkenyl, alkynyl,    haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,    heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl    any of which may be optionally independently substituted as valence    allows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ;-   R¹¹, R¹², R¹² ^(a) and R¹³ are independently    -   (a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,        (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of        which may be optionally independently substituted as valence        allows with one or more Z¹ ^(e) , Z² ^(e) and Z³ ^(e) ;-   R¹⁴ is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,    (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,    (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which    may be optionally independently substituted as valence allows with    one or more Z¹ ^(e) , Z² ^(e) and Z³ ^(e) ;-   Z¹ ^(a-) ¹ ^(e) , Z² ^(a-) ² ^(e) , and Z³ ^(a-) ³ ^(e) are optional    substituents at each occurrence independently selected from —W¹—V¹;    —W²—V²; —W³—V³; —W⁴—V⁴; —W⁵—V⁵;-   where W¹⁻⁵ are independently    -   (1) a bond    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of        which may be optionally independently substituted as valence        allows with one or more V¹⁻⁵; or-   where V¹⁻⁵ are independently    -   (1) H;    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of        which may be optionally independently substituted as valence        allows with one or more of groups (3)-(25) of V¹⁻⁵;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (24) oxo;    -   (25) —U¹—Y⁵;-   Z^(1f), at each occurrence, is independently selected from    -   (1) cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, optionally        substituted as valence allows with one or more of groups (2)        to (25) of Z^(1f);    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—S—Y⁵,    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY²Y³,    -   (11) —U¹—N(Y⁴)—C(O)—Y¹,    -   (12) —U¹—N(Y⁴)—C(S)—Y¹,    -   (13) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (14) —U¹—N(Y⁴)—C(S)—NY²Y³,    -   (15) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (16) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (18) —U¹—C(O)—NY²Y³,    -   (19) —U¹—OC(O)—NY²Y³    -   (20) —U¹—S(O)₂—N(Y⁴)—Y¹,    -   (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,    -   (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,    -   (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,    -   (24) oxo;    -   (25) —U¹—Y⁵;-   V^(1a) is independently hydrogen, alkyl, —CN, —C(O)Y¹, —S(O)₂Y⁵,    S(O)₂NY²Y³;-   Y¹, Y², Y³, Y⁴ and Y⁵    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl, any of which may be optionally independently        substituted as valence allows with one or more Z⁴, Z⁵ and Z⁶; or    -   (2) Y² and Y³ may together be alkylene or alkenylene, completing        a 3- to 8-membered saturated or unsaturated ring together with        the atoms to which they are attached, or    -   (4) Y² and Y³ together with the nitrogen atom to which they are        attached may combine to form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷        are each independently H or alkyl; and-   Z⁴, Z⁵, and Z⁶ are optional substituents at each occurrence    independently selected from    -   (1) H    -   (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,        cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,        (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,        (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl;    -   (3) —U¹—O—Y^(5a),    -   (4) —U¹—S—Y^(5a),    -   (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y^(5a) where t is 1 or 2,    -   (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y^(5a),        -   (7) —U¹-halo,    -   (8) —U¹-cyano,    -   (9) —U¹-nitro,    -   (10) —U¹—NY² ^(a) Y³ ^(a) ,    -   (11) —U¹—N(Y⁴ ^(a) )—C(O)—Y^(1a),    -   (12) —U¹—N(Y⁴ ^(a) )—C(S)—Y^(1a),    -   (13) —U¹—N(Y⁴ ^(a) )—C(O)—NY² ^(a) Y³ ^(a) ,    -   (14) —U¹—N(Y⁴ ^(a) )—C(S)—NY² ^(a) Y³ ^(a) ,    -   (15) —U¹—N(Y⁴ ^(a) )—C(O)O—Y^(5a),    -   (16) —U¹—N(Y⁴ ^(a) )—S(O)₂—Y^(1a),    -   (17) —U¹—N(Y⁴ ^(a) )—S(O)₂—NY² ^(a) Y³ ^(a) ,    -   (18) —U¹—C(O)—NY² ^(a) Y³ ^(a) ,    -   (19) —U¹—OC(O)—NY² ^(a) Y³ ^(a)    -   (20) —U¹—S(O)₂—N(Y⁴ ^(a) )—Y^(1a),    -   (21) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—NY² ^(a) Y³ ^(a) ,    -   (22) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—Y^(1a),    -   (23) —U¹—C(═NV¹ ^(b) )—NY² ^(a) Y^(3a),    -   (24) oxo;    -   (25) —U¹—Y^(5a);-   V^(1b) is independently hydrogen, alkyl, —CN, —C(O)Y^(1a),    —S(O)₂Y^(5a), S(O)₂NY^(2a)Y^(3a);-   Y¹ ^(a) , Y² ^(a) , Y³ ^(a) , Y⁴ ^(a) and Y^(5a)    -   (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,        (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,        cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,        heterocyclo, (heterocylco)alkyl, heteroaryl, or        (heteroaryl)alkyl;-   U¹ is independently    -   (1) a single bond,    -   (2) alkylene,    -   (3) alkenylene, or    -   (4) alkynylene.

In another embodiment are compounds of formula (I) wherein the compoundsare selected from the compounds of the Examples.

Another embodiment is directed to pharmaceutical compositions containingat least one compound of formula (I) and a pharmaceutically-acceptablecarrier or diluent, for use in treating inflammatory and immune diseasesor cancer. Also included within the invention are methods of treatingsuch diseases comprising administering to a mammal in need of suchtreatment an effective amount of at least one compound of formula (I).

In another embodiment, R⁶ is phenyl substituted with 0-3 Z¹ ^(d) , Z²^(d) and Z³ ^(d) .

In another embodiment, R⁶ is SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) ,C(O)R⁷ ^(a) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .

In another embodiment, R¹ is hydrogen, methyl, or ethyl.

In another embodiment, R² is hydrogen.

In another embodiment, R¹ is selected from hydrogen, C₁₋₃ alkyl, andC₂₋₃ alkenyl; and R² is hydrogen, alkyl, haloalkyl, or aryl.

In another embodiment, R³ and R⁴ are independently selected from

-   -   (a) hydrogen,    -   (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,        (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or        (heteroaryl)alkyl any of which may be optionally independently        substituted as valence allows with one or more Z¹ ^(b) , Z² ^(b)        and Z³ ^(b) ;    -   (c) —NR¹²R¹³; or    -   (d) R³ and R⁴ together with the nitrogen atom to which they are        attached combine to form a 3 to 8 membered heterocyclic ring        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) .

In another embodiment, R³ and R⁴ are independently selected from

-   -   (a) alkyl which may be optionally independently substituted as        valence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;        or    -   (b) —C(O)OR¹⁴, —C(O)R¹¹, —C(O)NR¹²R¹³, —SO₂R¹⁴, —SO₂NR¹²R¹³.

In another embodiment, R³ and R⁴ are independently selected from

-   -   (a) alkyl which may be optionally independently substituted as        valence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;        or        -   wherein Z¹ ^(b) , Z² ^(b) and Z³ ^(b) is H, heterocyclo,            heteroaryl, any of which may be optionally independently            substituted as valence allows with one or more Z⁴, Z⁵ and            Z⁶; or —U¹—NY²Y³,    -   (b) —C(O)OR¹⁴, —C(O)R¹¹, —C(O)NR¹²R³, —SO₂R⁴, —SO₂NR¹²R¹³.

In another embodiment, R³ and R⁴ are independently selected fromhydrogen, alkyl, (hydroxy)alkyl, or (heteroaryl)alkyl any of which maybe optionally independently substituted as valence allows with 1-2 Z¹^(b) , Z² ^(b) and Z³ ^(b) ; —NR¹²R¹³; or R³ and R⁴ together with thenitrogen atom to which they are attached combine to form a 3 to 8membered heterocyclic ring optionally independently substituted asvalence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;

-   -   Z¹ ^(b) , Z² ^(b) and Z³ ^(b) are selected from hydrogen, alkyl,        —U¹—O—Y⁵, —U¹, —NY²Y³, and    -   U¹ is a single bond or alkylene,

In another embodiment, R³ and R⁴ are independently selected fromhydrogen, alkyl, substituted as valence allows with 0-2 Z¹ ^(b) , Z²^(b) and Z³ ^(b) .

In another embodiment R⁵ is selected from —NR³R⁴.

In another embodiment R⁵ is hydrogen.

In another embodiment,

-   R⁶ is selected from    -   a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, and haloalkyl, any of which may be        optionally independently substituted as valence allows with one        or more as valence allows Z^(1f);    -   (c) aryl, heteroaryl, which may be further substituted with with        one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (d) —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .

In another embodiment,

-   R⁶ is selected from    -   (a) hydrogen, or    -   (c) aryl, heteroaryl, which may be further substituted with with        one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (d) —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .

In another embodiment,

-   R⁶ is selected from    -   (a) hydrogen, or    -   (c) phenyl, or pyridyl, which may be further substituted with        with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (d) —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .

In another embodiment,

-   R⁶ is selected from    -   a) hydrogen, or    -   (b) alkyl, alkenyl, alkynyl, and haloalkyl, any of which may be        optionally independently substituted as valence allows with one        or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ;    -   R⁶ is    -    which may be further substituted with with one or more Z¹ ^(d)        , Z² ^(d) and Z³ ^(d) .    -   In another embodiment, R⁶ is    -    which may be further substituted with with one or more Z¹ ^(d)        , Z² ^(d) and Z³ ^(d) ,    -   and Z^(1d) is selected from        -   (a) cyano, halo, —OH, —OY⁵, —U¹—NY²Y³, —C(O)_(t)H,            —C(O)_(t)Y, —S(O)_(t)Y⁵;        -   (b) alkyl or alkoxy optionally substituted with one or more            cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y,            —U¹—N(Y⁴)—C(O)—Y¹, —U¹—N(Y⁴)—C(O)—NY²Y³, —U¹—N(Y⁴)—C(O)O—Y⁵,            —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,            —S(O)_(t)Y, —U¹-heteroaryl.-   In another embodiemtn, Z^(1d), Z^(2d) and Z^(3d) are optional    substituents independently selected from    -   (a) cyano, halo, —OH, —OY⁵, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y¹,        —U¹—C(O)—NY²Y³, —S(O)_(t)Y⁵;    -   (b) alkyl or alkoxy optionally substituted with one or more        cyano, halo, —OH, —OY⁵, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y¹,        —U¹—C(O)—NY²Y³, —OC(O)—NY²Y³, OC(O)—OY⁵, —U¹—N(Y⁴)—C(O)—Y¹,        —U¹—N(Y⁴)—C(O)—NY²Y³, —U¹—N(Y⁴)—C(O)O—Y⁵, —N(Y⁴)—S(O)₂—Y¹,        —N(Y⁴)—C(O)—C(O)—NY²Y³, —N(Y⁴)—C(O)—C(O)—OY⁵, —U¹—N(Y⁴)—C(═NV¹        ^(a) )—NY²Y³, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹, —S(O)_(t)Y,        —U¹-heteroaryl, or U1-heterocyclo, wherein heteroaryl and        heterocyclo are substituted as valence allows with one or more        of groups (3)-(28) of V¹⁻⁵.

In another embodiment, Y⁵ is H or alkyl, wherein the alkyl is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and hexyl;

Y² and Y³ are independently selected from alkyl wherein the alkyl isselected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl,pentyl, and hexyl.

In another embodiment, R³ and R⁴ are independently selected fromhydrogen, alkyl, wherein the alkyl is selected from methyl, ethyl,propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl, and hexyl;(hydroxy)alkyl, or (heteroaryl)alkyl, wherein (heteroaryl)alkyl is(tetrazolyl)methyl; any of which may be optionally independentlysubstituted with 1 Z¹ ^(b) ; —NR¹²R¹³; or R³ and R⁴ together with thenitrogen atom to which they are attached combine to form a 3 to 8membered heterocyclic ring, wherein the ring is selected frompiperidinyl, and morpholinyl, optionally independently substituted with1 Z¹ ^(b) .

In another embodiment, R³ is hydrogen;

R⁴ is alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl,(heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyl and of which may beoptionally independently substituted as valence allows with one or moreZ¹ ^(b) , Z² ^(b) and Z³ ^(b) ;

alternatively, R³ and R⁴ together with the nitrogen atom to which theyare attached combine to form a 3 to 6 membered heterocyclic ringselected from piperidinyl, morpholinyl, pyrrolidinyl, and azetidinyl;optionally independently substituted as valence allows with one or moreZ¹ ^(b) , Z² ^(b) and Z³ ^(b) .

In another embodiment, R⁶ is

-   -   (a) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,        (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or        (heteroaryl)alkyl any of which may be optionally independently        substituted as valence allows with one or more Z¹ ^(d) , Z² ^(d)        and Z³ ^(d) ; or    -   (b) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , C(O)R⁷ ^(a) ,        —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .

In another embodiment, R⁶ is

-   -   (a) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl,        (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or        (heteroaryl)alkyl any of which may be optionally independently        substituted as valence allows with one or more Z¹ ^(d) , Z² ^(d)        and Z³ ^(d) ; or    -   (b) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , C(O)R⁷ ^(a) ,        —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ;        wherein Z¹ ^(d) , Z² ^(d) and Z³ ^(d) is —W⁴—V⁴; where W⁴ is        independently    -   (1) a bond    -   (2) alkyl, (hydroxy)alkyl, alkenyl, haloalkyl, heteroaryl, or        (heteroaryl)alkyl; and        where V⁴ is independently    -   (1) H    -   (2) aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,        heteroaryl, or (heteroaryl)alkyl any of which may be optionally        independently substituted as valence allows with one or more of        groups (3)-(15) of V¹⁻⁵;    -   (3) —U¹—O—Y⁵,    -   (4) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2,    -   (5) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵,    -   (6) —U¹-halo,    -   (7) —U¹—NY²Y³,    -   (8) —U¹—N(Y⁴)—C(O)—Y¹,    -   (8) —U¹—N(Y⁴)—C(O)—NY²Y³,    -   (10) —U¹—N(Y⁴)—C(O)O—Y⁵,    -   (11) —U¹—N(Y⁴)—S(O)₂—Y¹,    -   (12) —U¹—N(Y⁴)—S(O)₂—NY²Y³,    -   (13) —U¹—C(O)—NY²Y³,    -   (14) —U¹—OC(O)—NY²Y³    -   (15) —U¹—S(O)₂—N(Y⁴)—Y¹; and        U¹ is a bond.

In another embodiment, compounds of formula (I) wherein

-   -   R⁶ is    -    which may be further substituted with with one or more Z¹ ^(d)        , Z² ^(d) and Z³ ^(d) .

In another embodiment, R⁶ is

-   -   (a) alkynyl optionally substituted with Z¹ ^(d) where Z¹ ^(d) is        aryl which may be further optionally independently substituted        with one or more cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,        —C(O)_(t)Y, or, —S(O)_(t)Y;    -   (b) aryl optionally independently substituted as valence allows        with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or    -   (c) —SR^(7a), —SO₂R¹⁰, or —SO₂NR⁸ ^(b) R⁹ ^(b) ;        -   Z¹ ^(b) , Z² ^(b) and Z³ ^(b) are optional substituents            independently selected from —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,            —C(O)_(t)Y, —U¹—N(Y⁴)—C(O)—Y¹, or —U¹—N(Y⁴)—C(O)O—Y⁵.

In another embodiment

R⁶ is

-   (a) alkynyl optionally substituted with Z¹ ^(d) where Z¹ ^(d) is    aryl which may be further optionally independently substituted with    one or more cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,    —C(O)_(t)Y, or, —S(O)_(t)Y;-   (b) aryl optionally independently substituted as valence allows with    one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or-   (c) —SR^(7a), —SO₂R¹⁰, or —SO₂NR⁸ ^(b) R⁹ ^(b) ;-   Z¹ ^(b) , Z² ^(b) and Z³ ^(b) are optional substituents    independently selected from —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,    —C(O)_(t)Y, —U¹—N(Y⁴)—C(O)—Y¹, or —U¹—N(Y⁴)—C(O)O—Y⁵,    -   where-   U¹ is a bond or alkylene;-   Z¹ ^(C) is    -   (a) —OY where Y is aryl, or    -   (b) aryl optionally substituted with —OH or —OY where Y is        alkyl;-   Z¹ ^(d) , Z² ^(d) and Z³ ^(d) are optional substituents    independently selected from    -   (a) cyano, halo, —OH, —OY, —C(O)_(t)H, —C(O)_(t)Y, —S(O)_(t)Y,        or        -   (b) alkyl or alkoxy optionally substituted with one or more            cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y,            —S(O)_(t)Y, —U¹—N(Y⁴)—C(O)—Y¹, —U¹—N(Y⁴)—C(O)—NY²Y³,            —U¹—N(Y⁴)—C(O)O—Y⁵, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³,            —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹, —U¹—N(Y⁴)—C(O)—Y¹,            —U¹—N(Y⁴)—C(O)—Y¹, or —U¹—N(Y⁴)—S(O)₂—Y¹,            -   where-   U¹ is a bond or alkylene.

In another embodiment

R⁶ is

-   (a) alkynyl optionally substituted with Z¹ ^(d) where Z¹ ^(d) is    phenyl which may be further optionally independently substituted    with 0-1 cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y,    or, —S(O)_(t)Y;-   (b) phenyl optionally independently substituted as valence allows    with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or-   (c) —SR^(7a);-   Z¹ ^(b) , Z² ^(b) and Z³ ^(b) are optional substituents    independently selected from —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,    —C(O)_(t)Y, —U¹—N(Y⁴)—C(O)—Y¹, or —U¹—N(Y⁴)—C(O)O—Y⁵,    -   where-   U¹ is a bond or alkylene, wherein alkylene is selected from    methylene, ethylene, propylene, and butylene;-   Z¹ ^(C) is    -   (a) —OY where Y is phenyl, or    -   (b) phenyl optionally substituted with 0-1 —OH or —OY where Y is        alkyl selected from methyl, ethyl, propyl, i-propyl, butyl,        i-butyl, t-butyl, pentyl, hexyl;-   Z¹ ^(d) , Z² ^(d) and Z³ ^(d) are optional substituents    independently selected from    -   (a) cyano, halo, —OH, —OY, —C(O)_(t)H, —C(O)_(t)Y, —S(O)_(t)Y,        or    -   (b) alkyl or alkoxy optionally substituted with one or more        cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y,        —S(O)_(t)Y, —U¹—N(Y⁴)—C(O)—NY²Y³, —U¹—N(Y⁴)—C(O)O—Y⁵,        —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹,        —U¹—N(Y⁴)—C(O)—Y¹, —U¹—N(Y⁴)—C(O)—Y¹, or —U¹—N(Y⁴)—S(O)₂—Y¹,        -   where-   U¹ is a bond or alkylene, wherein alkylene is selected from    methylene, ethylene, propylene, and butylene.    In another embodiment, R⁶ is    -   (a) alkynyl optionally substituted with Z^(1d) where Z^(1d) is        aryl which may be further optionally independently substituted        with one or more cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,        —C(O)_(t)Y, or, —S(O)_(t)Y; or    -   (b) aryl optionally independently substituted as valence allows        with one or more Z^(1d), Z^(2d) and Z^(3d);    -   (c) heteroaryl optionally independently substituted as valence        allows with one or more Z^(1d), Z^(2d) and Z^(3d); or    -   (d) —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .        In another embodiment, R⁷ is hydrogen, alkyl, alkenyl, alkynyl,        or haloalkyl.        In another embodiment, R⁷ is hydrogen.

In another embodiment, Y¹, Y², Y³, and Y⁴ are independently selectedfrom hydrogen, alkyl, wherein alkyl is selected from alkyl is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, t-butyl, pentyl,and hexyl; aryl wherein aryl is phenyl, (aryl)alkyl.

Another embodiment is directed to a compound of Formula (I), wherein thecompound is selected from the compounds of the Examples or of Tables.

Another embodiment is directed to a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of Formula (I).

Another embodiment is directed to a method of treating an inflammatoryor immune disease or disorder comprising administering to a mammal inneed thereof a therapuetically-effective amount of at least one compoundof formula (I).

Another embodiment is directed to a method of treating cancer comprisingadministering to a mammal in need thereof a therapuetically-effectiveamount of at least one compound of formula (I)

Another embodiment is directed to a method of treating an inflammatoryor immune disease or disorder selected from, rheumatoid arthritis,asthma, inflammatory bowel disease, chronic obstructive pulmonarydisease, and psoriasis.

Another embodiment is directed to the use of a compound of Formula (I)in the preparation of a medicament for the treatment of an inflammatoryor immune disease.

Another embodiment is directed to the use of a compound of Formula (I)in the preparation of a medicament for the treatment of cancer.

Another embodiment is directed to the use of a compound of Formula (I)in the preparation of a medicament for the treatment of an inflammatoryor immune disease.

Another embodiment is directed to the use of a compound of Formula (I)in the preparation of a medicament for the treatment of cancer.

Another embodiment is directed to the use of a compound of Formula (I)in the preparation of a medicament for the treatment of an inflammatoryor immune disease, wherein the disease is selected from, rheumatoidarthritis, asthma, inflammatory bowel disease, chronic obstructivepulmonary disease, and psoriasis.

Another embodiment is directed to the use of a compound of Formula (I)for use in therapy.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects and embodiments ofthe invention noted herein. It is understood that any and allembodiments of the present invention may be taken in conjunction withany other embodiment to describe additional embodiments of the presentinvention. Furthermore, any elements of an embodiment are meant to becombined with any and all other elements from any of the embodiments todescribe additional embodiments.

DEFINITIONS

The following are definitions of terms used in this specification. Theinitial definition provided for a group or term herein applies to thatgroup or term throughout the present specification, individually or aspart of another group, unless otherwise indicated.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's or ringatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substitent is keto (i.e., ═O), then 2hydrogens on the atom are replaced. The term “optionally independentlysubstituted as valence allows”, as used herein, means that the any oneor more hydrogens on the designated variable is independently replacedwith a selection from the indicated group, provided that the designatedvariable's normal valency is not exceeded, and that the substitutionresults in a stable compound.

When any variable (e.g., R^(a)) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R^(a), then saidgroup may optionally be substituted with up to two R^(a) groups andR^(a) at each occurrence is selected independently from the definitionof R^(a). Also, combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

It will be appreciated that the compounds of the present invention maycontain one or more asymmetrically substituted carbon atom, and may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated. All tautomers of shown ordescribed compounds are also intended.

The term “alkyl” as used herein by itself or as part of another grouprefers to straight and branched chain hydrocarbons, containing 1 to 20carbons, alternatively, 1 to 10 carbons, or 1 to 8 carbons, such asmethyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl,hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like. Lower alkyl groups, thatis, alkyl groups of 1 to 4 carbon atoms, are an alternative embodiment.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

The term “alkenyl” as used herein by itself or as part of another grouprefers to straight or branched chain radicals of 2 to 20 carbons,alternatively, 2 to 12 carbons, or 1 to 8 carbons in the normal chain,which include one to six double bonds in the normal chain, such asvinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl,2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl,3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl,and the like.

The term “alkynyl” as used herein by itself or as part of another grouprefers to straight or branched chain hydrocarbon groups having 2 to 12carbon atoms, alternatively, 2 to 4 carbon atoms, and at least onetriple carbon to carbon bond, such as ethynyl, 2-propynyl, 3-butynyl,2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl,3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl,4-dodecynyl and the like.

When the term “alkyl” is used together with another group, such as in“(aryl)alkyl”, this conjunction is meant to refer to a substituted alkylgroup wherein at least one of the substituents is the specifically namedgroup in the conjunction. For example, “(aryl)alkyl” refers to asubstituted alkyl group as defined above wherein at least one of thesubstituents is an aryl, such as benzyl.

Where alkyl groups as defined above have single bonds for attachment totwo other groups, they are termed “alkylene” groups. Similarly, wherealkenyl groups as defined above and alkynyl groups as defined above,respectively, have single bonds for attachment to two other groups, theyare termed “alkenylene groups” and “alkynylene groups” respectively.Examples of alkylene, alkenylene and alkynylene groups include:

and the like. Alkylene groups may be optionally independentlysubstituted as valence allows with one or more groups provided in thedefinition of Z¹.

The term “cycloalkyl” as used herein by itself or as part of anothergroup refers to saturated and partially unsaturated (containing 1 or 2double bonds) cyclic hydrocarbon groups containing 1 to 3 rings,including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containinga total of 3 to 20 carbons forming the rings, alternatively, 3 to 7carbons, forming the ring. The rings of multi-ring cycloalkyls may beeither fused, bridged and/or joined through one or more spiro union to 1or 2 aromatic, cycloalkyl or heterocyclo rings. Exemplary cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl,cycloheptadienyl,

and the like.

The term “cycloalkylene” as employed herein refers to a “cycloalkyl”group which includes free bonds and thus is a linking group such as

and the like.

One skilled in the field will understand that, when the designation“CO₂” is used herein, this is intended to refer to the group

The term “alkoxy” refers to an alkyl or substituted alkyl group asdefined above bonded through an oxygen atom (—O—), i.e., the groups—OR_(d), wherein R_(d) is alkyl or substituted alkyl.

The term “alkylthio” refers to an alkyl or substituted alkyl group asdefined above bonded through a sulfur atom (—S—), i.e., the groups—SR_(d), wherein R_(d) is alkyl or substituted alkyl.

The term “acyl” refers to a carbonyl group linked to an organic radical,more particularly, the group C(═O)R_(g), wherein R_(g) can be selectedfrom alkyl, alkenyl, substituted alkyl, or substituted alkenyl, asdefined herein.

The term “alkoxycarbonyl” refers to a carboxy group

linked to an organic radical (CO₂R_(g)), wherein R_(g) is as definedabove for acyl.

The term “halo” or “halogen” refers to chloro, bromo, fluoro and iodo.

The term “haloalkyl” means a substituted alkyl having one or more halosubstituents. For example, “haloalkyl” includes mono, bi, andtrifluoromethyl.

The term “haloalkoxy” means an alkoxy group having one or more halosubstituents. For example, “haloalkoxy” includes OCF₃.

The terms “ar” or “aryl” as used herein by itself or as part of anothergroup refer to aromatic homocyclic (i.e., hydrocarbon) monocyclic,bicyclic or tricyclic aromatic groups containing 6 to 14 carbons in thering portion (such as phenyl, biphenyl, naphthyl (including 1-naphthyland 2-naphthyl) and antracenyl) and may optionally include one to threeadditional rings (either cycloalkyl, heterocyclo or heteroaryl) fusedthereto. Examples include:

and the like.

The term “heteroaryl” as used herein by itself or as part of anothergroup refers to monocyclic and bicyclic aromatic rings containing from 5to 10 atoms, which includes 1 to 4 hetero atoms such as nitrogen, oxygenor sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl orheterocyclo ring, where the nitrogen and sulfur heteroatoms mayoptionally be oxidized and the nitrogen heteroatoms may optionally bequaternized. Examples of heteroaryl groups include pyrrolyl, pyrazolyl,pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, triazinyl, indolyl, benzothiazolyl,benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridyl,dihydroisoindolyl, tetrahydroquinolinyl, carbazolyl, benzidolyl,phenanthrollinyl, acridinyl, phenanthridinyl, xanthenyl

and the like.

In compounds of formula (I), heteroaryl groups include

and the like, which optionally may be substituted at any availablecarbon or nitrogen atom.

The terms “heterocyclic” or “heterocyclo” as used herein by itself or aspart of another group refer to optionally substituted, fully saturatedor partially unsaturated cyclic groups (for example, 3 to 13 membermonocyclic, 7 to 17 member bicyclic, or 10 to 20 member tricyclic ringsystems, alternatively, containing a total of 3 to 10 ring atoms) whichhave at least one heteroatom in at least one carbon atom-containingring. Each ring of the heterocyclic group containing a heteroatom mayhave 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atomsand/or sulfur atoms, where the nitrogen and sulfur heteroatoms mayoptionally be oxidized and the nitrogen heteroatoms may optionally bequaternized. The heterocyclic group may be attached at any heteroatom orcarbon atom of the ring or ring system, where valance allows. The ringsof multi-ring heterocycles may be either fused, bridged and/or joinedthrough one or more spiro unions. Exemplary heterocyclic groups includeazetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl,isoxazolinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl,

and the like.

Heterocyclo groups in compounds of formula (I) include

which optionally may be substituted.

The term “ring” encompasses homocyclic (i.e., as used herein, all thering atoms are carbon) or “heterocyclic” (i.e., as used herein, the ringatoms include carbon and one to four heteroatoms selected from N, Oand/or S, also referred to as heterocyclo), where, as used herein, eachof which (homocyclic or heterocyclic) may be saturated or partially orcompletely unsaturated (such as heteroaryl).

Unless otherwise indicated, when reference is made to aspecifically-named aryl (e.g., phenyl), cycloalkyl (e.g., cyclohexyl),heterocyclo (e.g., pyrrolidinyl) or heteroaryl (e.g., imidazolyl),unless otherwise specifically indicated the reference is intended toinclude rings having 0 to 3, alternativley, 0 to 2, substituentsselected from those recited above for the aryl, cycloalkyl, heterocycloand/or heteroaryl groups, as appropriate.

The term “heteroatoms” shall include oxygen, sulfur and nitrogen.

The term “carbocyclic” means a saturated or unsaturated monocyclic orbicyclic ring in which all atoms of all rings are carbon. Thus, the termincludes cycloalkyl and aryl rings. The carbocyclic ring may besubstituted in which case the substituents are selected from thoserecited above for cycloalkyl and aryl groups.

When the term “unsaturated” is used herein to refer to a ring or group,the ring or group may be fully unsaturated or partially unsaturated.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of the formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases. Inaddition, when a compound of formula I contains both a basic moiety,such as, but not limited to an amine or a pyridine ring, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare also useful, e.g., in isolation or purification steps which may beemployed during preparation. Salts of the compounds of the formula I maybe formed, for example, by reacting a compound of the formula I with anamount of acid or base, such as an equivalent amount, in a medium suchas one in which the salt precipitates or in an aqueous medium followedby lyophilization.

Exemplary acid addition salts include acetates (such as those formedwith acetic acid or trihaloacetic acid, for example, trifluoroaceticacid), adipates, alginates, ascorbates, aspartates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as benzathines, dicyclohexylamines, hydrabamines[formed with N,N-bis(dehydro-abietyl)ethylenediamine],N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quaternized with agents such as loweralkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g., benzyl and phenethyl bromides), and others.

Compounds of the formula I, and salts thereof, may exist in theirtautomeric form, in which hydrogen atoms are transposed to other partsof the molecules and the chemical bonds between the atoms of themolecules are consequently rearranged. It should be understood that alltautomeric forms, insofar as they may exist, are included within theinvention. Additionally, inventive compounds may have trans and cisisomers and may contain one or more chiral centers, therefore existingin enantiomeric and diastereomeric forms. The invention includes allsuch isomers, as well as mixtures of cis and trans isomers, mixtures ofdiastereomers and racemic mixtures of enantiomers (optical isomers).When no specific mention is made of the configuration (cis, trans or Ror S) of a compound (or of an asymmetric carbon), then any one of theisomers or a mixture of more than one isomer is intended. The processesfor preparation can use racemates, enantiomers, or diastereomers asstarting materials. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatographic or fractional crystallization. The inventive compoundsmay be in the free or hydrate form.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention.

For example, pro-drug compounds of formula I may be carboxylate estermoieties. A carboxylate ester may be conveniently formed by esterifyingany of the carboxylic acid functionalities found on the disclosed ringstructure(s). Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and    Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K. Widder,    et. al. (Academic Press, 1985);-   b) A Textbook of Drug Design and Development, edited by    Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and    Application of Prodrugs,” by H. Bundgaard, at pp. 113-191 (1991);-   c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38    (1992);-   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, Vol.    77, p. 285 (1988); and-   e) N. Kakeya, et. al., Chem Phar Bull, Vol. 32, p. 692 (1984).

It should further be understood that solvates (e.g., hydrates) of thecompounds of formula I are also with the scope of the present invention.Methods of solvation are generally known in the art.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

It should further be understood that solvates (e.g., hydrates) of thecompounds of formula I are also contemplated to be within the scope ofthe present invention.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to inhibit IKK oreffective to treat or prevent inflammatory disorders.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Methods of Preparation

Compounds of Formula I may be prepared by reference to the methodsillustrated in the following Schemes I-V. As shown therein the endproduct is a compound having the same structural formula as Formula I.It will be understood that any compound of Formula I may be produced byScheme I-V by the suitable selection of reagents with appropriatesubstitution. Solvents, temperatures, pressures, and other reactionconditions may readily be selected by one of ordinary skill in the art.All documents cited are incorporated herein by reference in theirentirety. Starting materials are commercially available or readilyprepared by one of ordinary skill in the art. Constituents of compoundsare as defined herein or elsewhere in the specification.

The sequence described in Scheme I will produce compounds of Formula I.Nitration of 4-hydroxy pyridine, I-1 to provide the known compound I-2.followed by conversion to the corresponding known chloro-pyridine I-3.Subsequent addition of an amine such as methylamine provides thepreviously un-described compound I-4. Reduction of both nitro groups andsimultaneous chlorination of the intermediate triaminopyridine occurs ontreatment of I-4 with tin(II) chloride to produce I-5. This importantintermediate can be reacted with triethyl orthoformate to provide fusedimidazole I-6. Diazotization of the amine under reductive conditionsprovides imidazopyridine I-7 which reacts with amines such as methylamine, ethyl amine, para-methoxybenzyl amine etc. in highregioselectivity which after protection with Boc anhydride or similarreagent provides amino compound I-8. Substitution of the chloro groupwith an amine can be readily accomplished by what is commonly referredto as a Buchwald amination (for examples see Yin, J., Buchwald, S. L.,J. Am. Chem. Soc. 2002, 124(21) 6043-6048). Thus I-8 is reacted withbenzophenoneimine or lithium bistrimethylsilylamide (to directly produceI-10) in the presence of a palladium catalyst, preferably with the useof Xantphos® as a ligand to provide I-9 which is readily hydrolyzed toproduce amine I-10. Reaction of the aminopyridine I-10 withN-iodosuccinimide or other electrophillic iodine species such as I₂ withsilver triflate, will provide iodopyridine I-11. A Sonogashira reactionwith intermediate I-11 and an acetylene provides intermediate I-12,which can readily undergo 5 endo-dig cyclization in the presence of abase or palladium catalyst to provide I-13. Removal of the Bocprotecting group with trifluoroacetic acid with or without the presenceof a scavenger such as anisole, or thioanisole provides I-14 which is acompound of Formula I.

Entry into compounds substituted at the 8-position of this system can beenvisioned to arise by electrophillic aromatic substitution reactionssuch as halogenation followed by subsequent transformations as depictedin Scheme II. Thus I-14 can readily undergo halogenation withN-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide to produceintermediate II-1 (bromo depicted). This versatile intermediate canundergo several transformations. Of particular interest to thisapplication is reaction with zinc cyanide in the presence of palladium,or copper cyanide to produce II-2 which is a compound of Formula I. Alsoof interest is carbonylation of II-1 to produce II-4, which is also acompound of Formula I. Alternatively II-4 can arise from thecarbonylative cyclization of I-12 in the presence of carbon monoxidegas, and a palladium catalyst in the presence of a suitable alcohol toproduce II-3 which is readily deprotected with trifluoroacetic acid withor without the presence of anisole, or thioanisole to provide II-4.

Alternatively a potentially more versatile route to compounds of FormulaI is described in Scheme III. III-1 can be prepared as described inScheme I using trimethylsilylacetylene as the reacting partner with I-11and proceeding through the cyclization step. Protection of the indolenitrogen can be accomplished with a suitable base such as sodium hydridefollowed by addition of ditertbutyldicarbonate ((Boc)₂O) to provideIII-2. Selective deprotonation with n-butyl lithium, or with the milderbase lithium diisopropylamide (see Vasquez, E. et. al. J. Org. Chem.2002, 67 7551-7552.) followed by reaction with a boronating reagent suchas triisopropylborate which after hydrolysis provides the versatileintermediate III-3. Intermediate III-3 is able to react with a widevariety of substrated in what is commonly referred to as a Suzukicoupling to produce III-4 which are compounds of Formula I.

Substitution on the pyrrole nitrogen can be accomplished in generaleither by direct synthesis using the Buchwald synthesis with the desiredamine as described in Scheme I using intermediate I-8. In some case itmay be more convenient to perform the desired substitution as describedin Scheme IV. Thus deprotonation with a suitable base such as sodiumhydride, sodium bis(trimethylsilyl)amide, potassium butoxide, cesiumcarbonate and the like.

In general substitution at the 4-position of the heterocycle can beenvisioned to arise from the active chlorine substituent in intermediateI-7. In some instances it is more convenient to modify the route to theheterocycle. One such instance is described in Scheme V.

Thus commercially available 4-chloro-3-nitropyridine can undergo what iscommonly referred to as a vicarious nucleophillic substitution witheither hydroxylamine or ammonia in the presence of potassiumpermanganate to provide V-2. Protection of the amine as the Bocderivative can be assisted by the use of DMAP as the base to provideV-4. Reduction of the nitro group can be accomplished by a variety ofmethods generally known such as metal reductions such as zinc, iron, andthe like, or alternatively using hydrogen gas at a pressure ofatmospheric to 40 psi in the presence of a catalyst such as Palladium oncharcoal, platinum oxide, and the like to produce intermediate V-5.Reaction of the diamine V-5 with triethylorthoformate will provide V-6,which after removal of the protecting group using trifluoroacetic acidproduces amine V-7. Iodination of V-7 with N-iodosuccinimide or iodinein the presence of a catalyst such as silver triflate will produce V-8.Reaction of the iodoamine species in a manner similar to that describedin Schemes 1-4 will provide V-9.

EXAMPLES

The following examples illustrate preferred embodiments of the presentinvention and do not limit the scope of the present invention which isdefined in the claims. Abbreviations employed in the Examples aredefined below. Compounds of the Examples are identified by the exampleand step in which they are prepared (e.g., “A1.1” denotes the titlecompound of step 1 of Example A1), or by the example only where thecompound is the title compound of the example (for example, “A2” denotesthe title compound of Example A2).

Abbreviations

-   Ac Acetyl-   AcOH Acetic acid-   aq. Aqueous-   CDI Carbonyldiimidazole-   Bn Benzyl-   Bu Butyl-   Boc tert-butoxycarbonyl-   DIEA Diisopropylethylamine-   DMAP Dimethylaminopyridine-   DMA N,N-Dimethylacetamide-   DMF dimethylformamide-   DMSO Dimethylsulfoxide-   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   EtOAc Ethyl acetate-   Et Ethyl-   EtOH Ethanol-   H Hydrogen-   h Hours-   i iso-   HPLC High pressure liquid chromatography-   HOAc Acetic acid-   HOBT 1-Hydroxybenzotriazole-   Lawesson's Reagent    [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2-4-disufide-   LC liquid chromatography-   Me Methyl-   MeOH Methanol-   min. Minutes-   M⁺ (M+H)⁺-   M⁺¹ (M+H)⁺-   MP Melting point-   MS Mass spectrometry-   n normal-   PhCONCS Benzyolyisothiocyanate-   Pd/C Palladium on carbon-   Ph Phenyl-   Pr Propyl-   PSI Pounds per square inch-   Ret Time Retention time-   rt or RT Room temperature-   sat. Saturated-   S-Tol-BINAP (S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binapthyl-   t tert-   TFA Trifluoroacetic acid-   THF Tetrahydrofuran-   Phenominex Phenominex, Macclesfield, Cheshire, UK-   Xantphos® (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine]-   YMC YMC, Inc, Wilmington, N.C. 20403    HPLC conditions used to determine retention times;    LCMS conditions=A:    2 min gradient 0-100% B in A (A; 0.1% TFA in 90/10 water/methanol;    B; 0.1% TFA in 10/90 water/methanol) using a Phenominex 4.6×30 mm    S-5 ODS column    LCMS conditions=B:    4 min gradient 0-100% B in A (A; 0.1% TFA in 90/10 water/methanol;    B; 0.1% TFA in 10/90 water/methanol) using a Waters Sunfire C18    (4.6×50 mm)    Condition C:    HPLC: Column: YMC S5 ODS 4.6×50 mm; Gradient time: 4 min; Flow    rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.2% H3PO4; Solvent    B=90% MeOH—10% water—0.2% H3PO4; Start % B=0; Final % B=100.    Condition D:    Chiral HPLC: Column AD 4.6×250 mm; Hexanes/MeOH/Isopropanol (84/8/8)    (Isocratic).    Condition E:    Chiral HPLC: Column Chiralpak AD 10 um 4.6×250 mm; Percent B=60%    Isocratic; Flow rate=1 ml/min; Solvent A=Heptane; Solvent B=50%    MeOH—50% EtOH    Condition F:    Chiral HPLC: Column ChiralCEL OJ 10 um 4.6×250 mm; Percent B=20%    Isocratic; Flow rate=2 ml/min; Solvent A=CO₂; Solvent B MeOH—0.5%    DEA.    Condition G:    HPLC: Column: YMC 20×100 mm S-5; Gradient time: 10 min; Flow rate=20    ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90%    MeOH—10% water—0.1% TFA; Start % B=20; Final % B=100.    Condition H:    Chiral HPLC: Column ChiralCEL OD 10 um 4.6×250 mm; Percent B=35%    Isocratic; Flow rate=2 ml/min; Solvent A=CO₂; Solvent B MeOH—0.1%    DEA.    All systems utilized a detection wavelength of 254 nanometers or 220    nanometers.

In general reactions were conducted under a nitrogen atmosphere unlessotherwise noted.

Those experiments which specify they were performed in a microwave wereconducted either in a SmithSynthesizer™ manufactured by PersonalChemistry or a Discover™ microwave manufactured by CEM microwave. Thismicrowave oven generates a temperature which can be selected between60-250° C. The microwave automatically monitors the pressure which isbetween 0-290 PSI. Reaction times and temperatures are reported.

Example A1 1,6-dihydro-N,1-dimethyl-7-phenylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A1.1: 3,5-Dinitro-1H-pyridin-4-one

4-Hydroxypyridine (40.0 g, 0.42 mol) was added portionwise to fumingnitric acid (140 ml) and sulfuric acid (500 ml). The resulting mixturewas heated to 140° C. for 12 hours. The reaction mixture was cooled inan ice-bath and cautiously poured onto ice (500 ml). The yellow solidwhich precipitated was collected by filtration and dried under vacuum toyield A1.1 (70.0 g, 90%). ¹H-NMR (DMSO-d₆) δ: 4.06 (2H, s). HPLC (B):98.9%, ret. time=0.173 min., LC/MS (M−H)⁺=184.

A1.2: (3,5-Dinitro-pyridin-4-yl)methylamine

A1.1 (10.0 g, 0.051 mol) was added portionwise to a mixture ofphosphorus oxychloride (25 ml) and PCl₅ (17.0 g, 0.082 mol). Thereaction mixture was heated to reflux under a nitrogen atmosphere for 12hours. The reaction mixture was allowed to cool to room temperature andthe phosphorus oxychloride removed in vacuo. The residue was suspendedin dry THF (50 ml) and cooled to 0° C. Methylamine (32 ml, 2.0M in THF,0.064 mol) was added drop wise over 20 minutes under a nitrogenatmosphere and the resulting solution was allowed to warm to roomtemperature over 1 hour. The reaction mixture was evaporated in vacuoand the residue suspended in ethyl acetate (200 ml) which was thenfiltered and the filtrate evaporated in vacuo to leave the crudeproduct. The crude product was recrystallized from methanol (100 ml) togive A1.2 as a tan solid (7.2 g, 71% for two steps). HPLC (B): 98%, ret.time 1.58 min., LC/MS (M+H)⁺=199.

A1.3: 2,6-Dichloro-N′-methyl-pyridine-3,4,5-triamine

A solution of A1.2 (60.0 g, 0.30 mol) in concentrated hydrochloric acid(300 ml) was heated to 90° C. Tin (II) chloride (85.0 g, 0.45 mol) wasadded portionwise over 1 hour with vigorous effervescence noted for thefirst equivalent of tin chloride added. The reaction mixture was heatedfor a further hour before the addition of more tin chloride (28.0 g,0.15 mol) and continued heating for 2 more hours. The reaction mixturewas cooled to 0° C. and cautiously basified with concentrated ammoniumhydroxide (200 ml). The precipitated solid was filtered off and thefiltrate extracted with ethyl acetate (5×200 ml). The combined organicswere dried (MgSO4) and evaporated in vacuo to leave A1.3 as a brownsolid (28.0 g, 46%). HPLC (B): 98%, ret. time=1.58 min., LC/MS(M+H)⁺=208.

A1.4: 7-Amino-4,6-dichloro-1-methyl-1H-imidazo[4,5-c]pyridine

Triethylorthoformate (25.0 ml, 0.15 mol) was added in one portion to asuspension of A1.3 (28 g, 0.14 mol) in dry acetonitrile (400 ml). Thereaction mixture was heated to reflux for 4 hours and then cooled toroom temperature. The reaction mixture was evaporated in vacuo to leaveA1.4 as a brown powder. ¹H-NMR (DMSO-d₆) δ: 8.20 (1H, s), 5.49 (2H, br.s), 4.07 (3H, s). HPLC (A): 98%, ret. time=0.78 min., LC/MS (M+H)⁺=218.

A1.5: 4,6-Dichloro-1-methyl-1H-imidazo[4,5-c]pyridine

A solution of sodium nitrite (5.28 g; 76.5 mmol) in water (17 ml) wasadded drop wise over 5 minutes to a stirred solution of A1.4 (11.3 g; 52mmol) in hypophosphorous acid (50 wt. % solution in water, 150 mL) at 0°C. to 5° C. The reaction mixture was allowed to warm to room temperatureand stirred for an additional 40 minutes. The mixture was cooled in anice bath (0° C. to 5° C.) and the pH was adjusted to >10 by the additionof aqueous sodium hydroxide (55 g in 100 mL of water). The resultingsuspension was filtered. The filter cake was rinsed with water andsuction dried to afford 9.9 g (97%) of A1.5 as a HPLC: 99%, ret.time=0.92 min., LC/MS (M+H)⁺=202.06 (204.04, 206.02).

Alternative Route to A1.5

A1.6: 2,6-Dichloro-4-methylamino-pyridine

Methylamine (8M solution in ethanol, 5 ml; 40 mmol) was added drop wiseto a stirred solution of commercially available 2,4,6-trichloropyridine(5 g; 27.4 mmol) in absolute ethanol (50 ml). After heating to 55-60° C.for 24 hr, the mixture was cooled to rt and concentrated. After addingwater (50 ml) to the residue, the resulting suspension was filtered andthe white filter cake was washed with water (3×10 ml). After air drying,the solid was suspended in dichloromethane (25 ml) and stirred for 10minutes. Filtration, rinsing with dichloromethane and drying afforded2.45 g (51%) of A1.6 as a white solid. HPLC (A): 95%, ret. time=1.16min., LC/MS (M+H)⁺=177.00 (178.99).

Alternate Preparation

2,4,6-Trichloropyridine (1800 g, 9.89 mol) was dissolved in ethanol(1800 mL). Methylamine 40% solution in ethanol (6.3 L) was added over 1h and 40 min maintaining the reaction temperature between 20-25° C. Thereaction was stirred for 14 hours at room temperature and concentrated.The product was filtered, washed with methyl t-butyl ether (1,500 ml)and dried to yield A1.6 (1200 g, 68%)

A1.7: 2,6-Dichloro-4-methylamino-3-nitro-pyridine

Solid A1.6 (3.5 g, 19 mmol) was added portionwise to stirredconcentrated sulfuric acid at 0° C. Effervescence was observed. 90%Fuming nitric acid (3.5 ml) was added drop wise at a rate thatmaintained the internal temperature below 6° C. After the addition wascomplete (45 minutes), the solution was stirred 10 minutes. The reactionmixture was poured onto ˜100 g of ice and the resulting aqueous mixturewas extracted with dichloromethane (3×100 ml). The combined organicswere washed with water (200 ml), dried (MgSO₄/Na₂SO₄) and concentrated.The residue was dissolved in concentrated sulfuric acid (25 ml) andstirred 30 minutes at rt. Pouring the reaction mixture into ice gave ayellow suspension that was filter and dried to afford 2.45 g (49%) ofA1.7 as a yellow solid. HPLC (A): 95%, ret. time=1.16 min., LC/MS(M+H)⁺=177.00 (178.99).

Alternate Preparation

Sulfuric acid (1.4 L) was cooled to 0° C. and A1.6 (700 g, 3.95 mol) wasadded portionwise over a period of 1.5 h while maintaining thetemperature between −5° C. and 0° C. Fuming nitric acid (700 mL) wasadded over 1 h while maintaining the reaction at 0° C. and the reactionwas stirred at 0° C. for one hour and poured onto ice. The reactionmixture was extracted with dichloromethane (3×3 L) and the solventremoved under reduced pressure to produceN-(2,6-dichloropyridin-4-yl)-N-methylnitramide (535 g 61%)

Caution—while N-(2,6-dichloropyridin-4-yl)-N-methylnitramide has beenprepared without incident such intermediates should be treated withcaution (such as avoid mechanical shock and heat and work behind ashield)

Sulfuric acid (1.1 L) was cooled to 0° C. The intermediate nitramide(535 g, 2.4 mol) was added portionwise to the sulfuric acid whilemaintaining the reaction temperature at 0° C. (˜1 h). The reactionmixture was stirred for 1 h. Analysis of an aliquot showed disappearanceof the nitramide. The reaction mixture was poured onto ice and after 1.5h the product was extracted into dichloromethane (3×2 L) and the solventremoved under reduced pressure (temp=35° C.). The residue wascrystallized by the addition of n-hexane and the solid collected toyield A1.7 (500 g, 81%)

A1.5: 4,6-Dichloro-1-methyl-1H-imidazo[4,5-c]pyridine

A mixture of A1.7 (2.4 g; 10.8 mmol), SnCl₂.2H₂O (9.7 g; 43 mmol) andconcentrated HCl (20 ml) in methanol (80 ml) was refluxed 1 hr. Afterremoving the volatiles in vacuo, the intermediate(3,4-diamino-2,6-dichloro-N⁴-methylpyridine) was dissolved in methanol(80 ml) and trimethylorthoformate (10 ml) was added. After refluxing 30minutes, additional trimethylorthoformate (10 ml) was added and heatingwas continued for 30 minutes. After removing the volatiles in vacuo, theresidue was partitioned between ethyl acetate (200 ml) and 2N NaOH (150ml). The organic layer was washed with 2N NaOH (150 ml) and brine (100ml). Drying (MgSO₄) and concentration afforded 2.12 g (97%) of A1.5 as atan solid. HPLC (A): 98%, ret. time=0.94 min., LC/MS (M+H)⁺=202.05(204.04, 206.02).

Alternate Preparation

Ammonium chloride (787 g) was added to water (5 L) at room temperature.Iron (1.0 kg, 18 mol) was added and the reaction mixture heated to 90°C. A1.5 (500 g, 2.25 mmol) was added portionwise over ˜1 h (frothingobserved). The reaction mixture was maintained at 90° C. for 1 hourafter which time TLC analysis of the reaction mixture showed no startingmaterial remaining. The reaction mixture was allowed to cool to 30° C.and ethyl acetate (5 L) was added to the reaction and the mixture wasfiltered to remove the iron. The layers were separated and the waterlayer washed with additional ethyl acetate. The organic layer wascombined and the solvent removed under reduced pressure to provide theintermediate (3,4-diamino-2,6-dichloro-N⁴-methylpyridine, 360 g, 83%),which was dissolved in ethanol (1,058 mL). Triethylorthoformate (1058mL, 6.37 mol) was added at room temperature and the reaction mixtureslowly heated to 80° C. The reaction mixture was maintained at 80° C.for ˜15 h and cooled to 50° C. and the solvent removed by distillationunder reduced pressure. n-Hexane was added and the product crystallizedand was collected by filtration and dried to yield A1.7 (336 g, 74%,based on A1.5).

A1.8: 4-Methylamino-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine

A mixture of A1.5 (9.9 g; 49 mmol) and methylamine (8M solution inethanol, 80 mmol, 100 ml) was heated to 82° C. for 24 hr. After removingthe volatiles in vacuo, the residue was triturated with water (30 mL),filtered and dried to afford 8.89 g (93%) of A1.8 as a tan solid. HPLC(A): 99%, ret. time=0.98 min., LC/MS (M+H)⁺=197.16 (199.06).

Alternate Preparation

A1.7 (260 g, 1.3 mol) and methylamine 40% in ethanol (3.0 L) were placedin an autoclave and heated between 110-120° C. for 3 h. The reactionmixture was allowed to cool to room temperature and the solvent wasremoved by distillation under reduced pressure. The residue wastriturated with water (15 L) and then washed with hexane (5 L) and driedto yield A1.8 (228 g, 90%).

A1.9:4-[N-(Methyl)-N-(tertbutyloxycarbonyl)amino]-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine

A mixture of A1.8 (8.89 g, 45.3 mmol) was dissolved in anhydrous THF (50mL) and cooled in a bath maintained at −78° C. Sodiumbis(trimethylsilyl)amide (1M solution in THF, 56 mL, 56 mmol) was addedover 10 min and the reaction mixture stirred at −78° C. for anadditional 25 minutes. Di-tert-butyl dicarbonate (10.4 g, 47.6 mmol) wasadded portionwise and the low temperature bath removed. The reactionmixture was stirred at room temperature for 16 h and the solvent removedunder reduced pressure. The crude product was dissolved in 250 mL ofethyl acetate and washed with water (2×100 mL) followed by brine (100mL). The organic layer was dried over magnesium sulfate, filtered andthe solvent removed under reduced pressure. The product was purified bysilica gel chromatography (100% ethyl acetate) to provide 9.07 g (68%)of A1.9 LCMS Ret time 2.51 min, M+H+=297.15.

Alternate Preparation

A1.8 (50 g, 0.26 mol) was dissolved in THF (2.5 L) and maintainedbetween −25° C. and −20° C. Sodium bis(trimethylsilyl)amide 1M solutionin THF (400 mL, 0.40 mol) was added over a period of 30 minutes. Thereaction mixture was maintained between −25° C. and −20° C. for 30 minand ditertbutyldicarbonate (140 g, 0.64 mol) was added over 30 minutes(a slight exotherm was observed). The reaction mixture was stirred at−20° C. for ˜3 h and the solvent removed under reduced pressure. Theresidue was partitioned between water (2 L) and ethyl acetate (3 L). Thelayers were separated and the aqueous layer was extracted withadditional ethyl acetate (1 L). The combined organic layers were washedwith brine. The organic layer was separated, dried and the solventremoved under reduced pressure to produce a crude solid which wasstirred for 1 h with n-hexane, filtered, washed with additional hexaneand dried to yield A1.9 (62 g, 82%).

A1.10: tert-Butyl6-(diphenylmethyleneamino)-1-methyl-1H-imidazo[4,5-c]pyridine-4-yl(methyl)carbamate

A1.9 (9.00 g, 30.64 mmol) was dissolved in dimethylacetamide (100 mL)and benzophenone imine (8.69 g, 46 mmol),tris(dibenzylidineacetone)dipalladium (0) (1.69 g, 1.84 mmol), Xantphos®(1.60 g, 2.76 mmol) and cesium carbonate (16 g, 49 mmol) were added. Thereaction mixture was heated to 115° C. for 5 h and allowed to cool toroom temperature. The reaction mixture was filtered and concentratedunder reduced pressure. The residue was diluted with water (100 mL) andstirred for 10 min. The solid was collected by filtration. Additionalproduct was obtained from evaporation of the solution and purificationby silica gel chromatography. The product was combined to yield 13.85 g(˜100%) of A1.10, M+H⁺ 442.24.

Alternate Preparation

A stream of argon was passed through N,N-Dimethylacetamide (480 mL) for30 min. A1.9 (40 g, 0.14 mol), benzophenone imine (33.5 mL, 0.20 mol),Xantphos® (1.60 g, 2.76 mmol), tris(dibenzylidineacetone)dipalladium (0)(9.5 g, 0.01 mol), and cesium carbonate (16 g, 49 mmol) were added.Argon was passed through the reaction mixture for and additional 20 min.The reaction mixture was then heated under an argon atmosphere at 110°C. for 8 h. The reaction mixture was cooled to room temperature,filtered and the solvent evaporated under reduced pressure. The residuewas triturated with methyl tert-butyl ether and dried to yield A1.10 (44g, 74%).

A1.11: tert-Butyl6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A1.10 (13.85 g, 30.6 mmol) was dissolved in THF (100 mL) and cooled inan ice bath. 1N HCl (64 mL) was added dropwise and stirred for anadditional 20 min. The organic layer was separated and set aside. Theaqueous layer was neutralized by the addition of sodium hydroxide andsaturated with sodium chloride and extracted with ethyl acetate (3×100mL). All organic layers were combined and concentrated. The residue wastriturated with anhydrous ether (100 mL) and filtered to provide 8.31 g(98%) of A1.11 M+H⁺=278.29.

Alternate Preparation

A1.10 (42 g, 0.095 mol) was suspended in THF (310 mL) and cooled in anice-salt bath. HCl (0.5 N, 392 mL) was added dropwise while maintainingthe reaction temperature between 0° C. to 5° C. (˜30 minutes). Thereaction mixture was washed with ethyl acetate (3×300 mL) and the layersseparated. The organic layer was basified with aqeous NaOH (18%solution) until pH 12 and extracted and evaporated to yield A1.11 (21 g,80%).

A1.12:tert-Butyl6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A1.11 (8.0 g, 28.9 mmol) was dissolved in acetonitrile (260 mL) andcooled in an ice bath. N-iodosuccinimide (6.87 g, 29 mmol) was addedportion wise with stirring. The reaction mixture was stirred for anadditional 30 min, then the solvent removed under reduced pressure. Theresidue was purified on silica gel column (ethyl acetate) to yield 8.73g (75%) of A1.12. M+H⁺=404.02.

Alternate Preparation

A1.11 (25.0 g, 90.2 mmol) was suspended in acetonitrile (700 mL) andcooled in an ice-ethanol bath. N-iodosuccinimide (NIS) (19.5 g, 84.7mmol) dissolved in acetonitrile (200 mL) was then added dropwise over 1hr to the suspension of A1.11 while maintaining the internal reactiontemperature to below 0° C. After 70 mL of NIS addition, the reactionmixture became homogeneous. After complete NIS addition, the reactionmixture was stirred at 0° C. for an additional 15 min before quenchingwith sodium hydrogen sulfite solution (2M, 500 mL added dropwise over 1hr at 0° C.). The organic layer was separated and evaporated in vacuo.The remaining aqueous layer was extracted with dichloromethane (3×300mL) and the combined organics were added to the original evaporatedresidue and once again evaporated in vacuo. This residue was taken up indichloromethane (500 mL) and washed with water (500 mL). The organiclayer was dried (Na₂SO₄) and stirred with decolorizing charcoal (5 g),before filtering and pre-absorbing on celite. Purification by columnchromatography (dichloromethane→ethyl acetate gradient) gave a yellowsolid (31.3 g) which was slurried in anhydrous methanol (40 mL), thenfiltered to give pure A1.12 (26.6 g). The filtrate was evaporated invacuo and the slurry/filter process repeated (2×) to give a total of29.4 g (81%) of A1.12. M⁺−100 (100%)=304.19, M⁺+H⁺=404.17, M⁺+Na=426.14.¹H NMR (400 MHz, DMSO) δ: 7.97 (s, 1H), 5.78 (s, 2H), 3.97 (s, 3H), 3.17(s, 3H), 1.31 (s, 9H).

A1.13: tert-Butyl6-amino-1-methyl-7-(2-phenylethynyl)-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

Copper iodide (5.0 mg, 0.025 mmol) and dichlorobis(triphenylphosphine)palladium (4.0 mg, 0.050 mmol) were each added in one portion to amixture of A1.12 (100 mg, 0.25 mmol), phenylacetylene (28 mg, 0.28 mmol)and triethylamine (0.11 ml, 0.75 mmol) in dichloromethane (0.5 ml) atroom temperature under a nitrogen atmosphere. The resulting mixture washeated to 40° C. for 24 hrs before cooling to room temperature andevaporating in vacuo. The residue was purified by column chromatographyusing ethyl acetate as eluent to give 62 mg of A1.13. LC/MS PhenomenexS5 4.6×30 mm (2 min gradient) Found: M+H=378.27 at 1.51 min

Alternate Preparation

A suspension of A1.12 (1.0 g, 248 mmol) in DMF (6.80 mL) was degassed bybubbling argon through the solvent. Phenylacetylene was added (0.68 mL,6.2 mmol), followed by dichlorobis(triphenyl-phosphine)palladium II(0.10 g, 0.149 mmol), copper (I) iodide (28.4 mg, 0.06 mmol), anddegasssed diisopropylamine (9.2 mL). The pressure tube was sealed andimmediately immersed in a 60° C. oil bath, and stirred for 30 min. Thereaction mixture was evaporated to dryness under vacuum. The crudeproduct was partitioned between EtOAc (45 mL) and water. Afterseparation, the EtOAc layer was washed with water, brine, dried(Na₂SO₄), and concentrated under reduced pressure to yield over 1.0 g ofa brown taffy. Flash chromatography on silica gel, eluting with ahexane: EtOAc gradient yielded 0.94 g, (98%) of A1.13 as a pale yellowpowder. HPLC (condition C): 92.9%, ret. Time 2.91 min., LC/MS(M+H)⁺=378.4.

A1.14 (Alternate Preparation): tert-butylmethyl(1-methyl-7-phenyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl)carbamate

Potassium tert-butoxide (2.91 mL of a 1.0M solution in THF, 2.91 mmol)was added to a solution of A1.13 (0.88 g, 2.33 mmol) in DMA (14.7 mL).The reaction solution was stirred at 80° C. for 35 min. Additionalpotassium tert-butoxide solution was added (0.35 mL, 0.35 mmol), andstirring at 80° C. was continued for 2 h. DMA was removed under vacuum.Water was added (20.0 mL), and after cooling to 0° C., the precipitatewas collected by filtration, rinsed with ice-water and dried undervacuum to yield 0.70 g (79.5%) of A1.14 as a pale tan solid HPLC (C):92.4%, ret. Time 2.76 min., LC/MS (M+H)⁺=378.27

A1: 1,6-dihydro-N,1-dimethyl-7-phenylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

Potssium tert-butoxide (1M in THF, 0.04 ml, 0.04 mmol) was addeddropwise to a solution of A1.13 (9.3 mg, 0.025 mmol) in NMP (0.4 ml)under a nitrogen atmosphere. The resulting mixture was heated to 80° C.for 2 hrs before cooling to room temperature, quenching with water (0.5ml) and extracting with ethyl acetate (3×2 ml). The combined organicswere dried (MgSO₄) and evaporated in vacuo. The residue (A1.14) wasimmediately dissolved in TFA and allowed to stir at room temperature for2 hrs before evaporating in vacuo and purifying by preparative HPLC toprovide A1 (3.2 mg) as an off-white solid. LC/MS Phenomenex S5 4.6×30 mm(2 min gradient) Found: M+H⁺=278.22 at 1.310 min. ¹H-NMR (MeOD) 8.05 (s,1H), 7.71-7.66 (m, 2H), 7.40-7.30 (m, 2H), 7.25-7.18 (m, 1H), 7.04 (s,1H), 4.04 (s, 3H) and 3.22 (s, 3H).

Example A23-[1,5-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]benzonitrile

A2.1: 3-(2-(trimethylsilyl)ethynyl)benzonitrile

To a solution of commercially available 3-iodobenzonitrile (25 g, 0.109mol), copper (I) iodide (2.08 g, 0.0109 mol), PdCl₂(PPh₃)₂ (3.82 g,0.0054 mol) and triethylamine (45.7 ml, 0.327 mol) in 250 of drydichloromethane was added 12.8 g (0.131 mol) of trimethylsilylacetylenedrop wise at 0° C. over a period of 10 min. The reaction mixture wasstirred at RT over night. The reaction mixture was diluted withadditional dichloromethane, filtered over Celite and the filtrate wasconcentrated. The crude material was purified by silica gel (60-120)column chromatography using 95:5 petrolium ether/ethyl acetate aseluent. A2.1 (20 g, 92%) was obtained as a brown solid ¹H NMR, 400 MHz,CDCl₃: 7.79 (s, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.43 (t, 1H), 0.26 (s,9H).

A2.2: 3-Ethynylbenzonitrile

To a solution of 20 g (0.01 mol) of A2.1 in 400 ml of methanol was addeda solution of 0.28 g (0.005 mol) of potassium hydroxide in 3 ml ofwater. The reaction mixture was stirred at RT for 1 hr. The reactionmixture was diluted with 600 ml water and extracted with ethyl acetate.The extract was washed with brine and concentrated. The crude productwas purified by 60-120 silica gel coloum using 5% of ethyl acetate inpetrolium ether to provide A2.2 (10.7 g, 84%) as an off white solid ¹HNMR, 400 MHz, CDCl₃: 7.78 (s, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.43 (t,1H), 3.21 (s, 1H).

A2.3: tert-Butyl6-amino-7-(2-(3-cyanophenyl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A1.12 (1.48 g, 3.66 mmol), dichlorobis(triphenylphosphine)palladium (155mg, 0.22 mmol), 3-ethynylbenzonitrile (A2.2) (930 mg, 7.32 mmol) andtriethylamine (12 mL) were added to N,N-dimethylformamide (8 mL). Thereaction mixture was heated at 90° C. for 50 min, cooled and the solventremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography using ethyl acetate as the eluent to provide 960mg (65%) of A2.3. M+H⁺=403.21.

Alternate Preparation

A1.12 (8.0 g, 19.85 mmol), dichlorobis(triphenylphosphine)palladium (840mg, 1.2 mmol), 3-ethynylbenzonitrile (A2.2) (3.2 g, 25.0 mmol) andtriethylamine (60 mL) were each added to N,N-dimethylformamide (40 mL),and nitrogen was bubbled through the resulting mixture for 5 min. Thereaction mixture was heated at 90° C. for 20 min under a nitrogenatmosphere before cooling to room temperature and evaporating thesolvent in vacuo. The residue was purified by silica gel columnchromatography using ethyl acetate as eluent to provide 6.5 g (81%) ofA2.3 HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.80 min,M+H⁺=403.21

A2.4:3-[1,6-dihydro-1-methyl-4-(N-tert-butyloxycarbonyl-N-methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]benzonitrile

A2.3 (960 mg, 2.38 mmol) was dissolved in dimethylacetamide (12 mL).Potassium t-butoxide, 1M in THF (2.6 ml, 2.6 mmol) was added and thereaction was heated in an oil bath maintained at 80° C. for 20 min. Thereaction was allowed to cool to room temperature and the solvent wasremoved under reduced pressure. The residue was purified by Silica gelcolumn chromatography using ethyl acetate as the eluent to yield 517 mg(54%) of A2.4. M+H⁺=403.34.

Alternate Preparation

A2.3 (6.8 g, 16.84 mmol) was dissolved in dimethylacetamide (85 mL).Potassium t-butoxide, (1M in THF, 16.94 ml, 16.94 mmol) was added andthe reaction heated in an oil bath maintained at 80° C. for 20 min. Thereaction was allowed to cool to room temperature and the solvent wasremoved under reduced pressure. The residue was purified by Silica gelcolumn chromatography using ethyl acetate as the eluent to yield 4.33 g(64%) of A2.4. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.80min, M+H⁺=403.34.

A2.5:3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]benzonitrile

A2.4 (12 mg, 30 mmol) was dissolved in a 1:1 mixture of TFA andmethylene chloride, and stirred for 1 h. The volatiles were removedunder reduced pressure and the residue purified by reverse phase columnchromatography to provide 6.8 mg (75%) of A2. LC/MS Phenomenex S5 4.6×30mm (2 min gradient) Found: M+H⁺=203.23 at 1.23 min. ¹H-NMR (d₆-DMSO):12.2 (br s, 1H), 8.32 (br s, 2H) 8.17-8.15 (m, 1H), 7.64-7.59 (m, 3H),7.45 (s, 1H), 4.09 (s, 3H), 3.04 (s, 3H).

Example A37-[3-(Aminomethyl)phenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-aminetrifluoacetate salt

A3.17-[3-(Aminomethyl)phenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-(t-butyloxycarbonylamine)

A2.4 (1.2 g, 2.9 mmol) was dissolved in ethanol (100 mL, 100% ethanol).The solution was saturated with ammonia gas. Raney nickel (one spatulafull ˜1 g) was washed with water followed by ethanol and then added tothe reaction mixture. A balloon of hydrogen gas was affixed to thereaction mixture and stirred at room temperature for 24 h. The productwas filtered and the solvent removed under reduced pressure to yieldA3.1 (1.14 g, 94%) M+H⁺=407.28.

Alternate Preparation

A2.4 (5.6 g, 13.9 mmol) was dissolved in ethanol (300 mL, 100% ethanol)pre-saturated with ammonia gas. Raney nickel (one spatula full ˜1 g) waswashed with water followed by ethanol and then added to the reactionmixture. A balloon of hydrogen gas was affixed to the reaction mixtureand stirred at room temperature for 18 h. The reaction mixture wasfiltered through celite and the solvent removed under reduced pressureto yield A3.1 (5.7 g, 98%). HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.28 min, M+H⁺=407.28.

A3.27-[3-(Aminomethyl)phenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-aminetrifluoacetate salt

A3.1 (1.14 g, 2.8 mmol) was dissolved in dichloromethane (3 mL) andcooled in an ice bath. Trifluoroacetic acid (3 mL) was added and thereaction mixture was allowed to warm to room temperature and stirred for30 min. The solvent was removed under reduced pressure to provide A3(1.32 g, 88%) M+H⁺=307.24. ¹H NMR (MeOD): δ 8.20 (br s 1H), 7.72-7.68(m, 3H), 7.46 (t, J=7 hz, 1H), 7.28 (d, J=7 hz, 1H), 7.18 (s, 1H). 4.17(s, 3H), 2.05 (s, 3H).

Example A4N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]acetamide,hydrochloride salt

A4.1:N-[3-[1,6-dihydro-1-methyl-4-(methyl-t-butyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]acetamide

A3.1 (30 mg, 0.074 mmol) was dissolved in methylene chloride (0.5 mL)triethyl amine (8.6 mg, 0.085 mmol) was added and the mixture cooled inan ice bath. Acetyl chloride (6.1 mg, 0.078 mmol) was added drop wiseand the reaction mixture was stirred for 10 min. Saturated sodiumbicarbonate (0.5 mL) was added and the mixture was stirred for anadditional 5 minutes, and the product was collected by filtration.

An additional lot was prepared at the same time using the same proceduredetailed above using A3.1 (420 mg, 1.03 mmol), triethyl amine (15 mg,1.55 mmol), acetyl chloride (10.3 mg, 1.34 mmol) and methylene chloride(7 mL). The product of the two lots were combined to yield 437 mg (88%)of A4.1. M+H⁺=449.18.

A4.2:N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]acetamide

A4.1 (437 mg, 0.98 mmol) was dissolved in methanol (15 mL). 4N HCl indioxane (5.4 mL) was added and the reaction mixture was heated in an oilbath for 4 hours. The solvent was removed under reduced pressure. Theproduct was triturated with anhydrous ether, filtered and dried undervacuum to provide 350 mg (94%) of A4 as a white solid. M+H⁺=349.33 ¹HNMR δ 8.25, (s, 1H), 7.75-7.65 (m, 2H), 7.45 (t, J=7 hz, 1H), 7.28 (d,J=7 hz, 1H), 7.21 (s, 1H), 4.19 (s, 3H), 2.05 (s, 3H).

Examples A5-A52

Examples A5-A52 was prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of the carboxylic acid in dimethylformamide (DMF) (0.038mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol inDMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq). The reactor was agitated for 10 minutes via orbital shaker.Then 150 uL of a solution of 0.2 molar amine in DMF (0.03 mmol; 1 eq)and diisopropylethylamine (0.150; 5 eq) was added to each reactor welland the reactor was agitated for 16 hours at 65° C. The library wasdried via centrifugal evaporation and BOC groups were removed by adding600 uL of a 30% by volume solution of trifluoroacetic acid (TFA) indichloromethane (DCM) to each reactor (that had a BOC group) and thereactor was agitated for 2 hours. The library was dried via centrifugalevaporation and was dissolved in 600 uL of DMF and 600 uL of methanol(MeOH). The entire contents for each reactor were transferred to an STRplate was was purified by standard preparative HPLC-MS (H₂O/MeOH/0.1%TFA, gradient 35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column)utilizing mass-directed fractionation. The purified sample wasreconstituted in 1:1/MeOH:DCE, transferred to a tared 2.5 mL plasticmicrotube, dried via centrifugal evaporation and weighed. The finalproduct was analyzed by HPLC-MS (H₂O/MeOH/0.1% TFA). Examples preparedby this method are described in Table A1. TABLE A1

HPLC Retention MS Ex. R Name (min) Reported A5

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-methyl- propanamide 2.39377.19 A6

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2,2- dimethyl propanamide2.56 391.2 A7

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1-methylcyclopropanecarboxamide 2.49 389.16 A8

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1-hydroxy-cyclopropanecarboxamide 2.18 391.13 A9

1-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- cyclopropanecarboxamide2.37 400.14 A10

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-hydroxy- acetamide 1.99365.16 A11

2-(acetylamino)-N-[[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-acetamide 1.98 406.15 A12

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-(dimethylamino)-acetamide 1.82 392.2 A13

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]butanediamide 1.99 406.17A14

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3-methyl butanamide 2.6391.2 A15

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3,3- dimethyl-butanamide2.76 405.21 A16

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4-methyl- pentanamide 2.82405.21 A17

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3- methoxy-propanamide 2.2393.15 A18

4-(aminosulfonyl)-N-[[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-butanamide 2.03 456.12 A19

2-chloro-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzamide 2.65 445.11 A20

3-chloro-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzamide 2.97 445.11 A21

4-chloro-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzamide 3.01 445.12 A22

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]benzeneacetamide 2.64 425.19A23

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]benzenepropanamide 2.81439.17 A24

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzenebutanamide 2.94453.17 A25

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3- thiophenecarboxamide2.57 417.11 A26

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4- thiazolecarboxamide 2.39418.08 A27

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4-methyl-1,2,3-thiadiazole-5- carboxamide 2.53 433.1 A28

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-5-methyl-3-isoxazolecarboxamide 2.5 416.14 A29

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1H- tetrazole-5-acetamide2.09 417.14 A30

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- cyclopropanecarboxamide2.66 375.12 A31

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1,2,3-thiadiazole-4-carboxamide 2.69 419.03 A32

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzamide 2.96 411.10 A33

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- alpha,alpha-dimethylbenzeneacetamide 3.23 453.13 A34

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-acetamide 1.74 364.42 A35

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2- (methylamino)-acetamide1.74 378.36 A36

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-, (2S)- propanamide 1.78378.36 A37

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-, (2R)- propanamide 1.77378.36 A38

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2- (methylamino)-, (2S)-propanamide 1.81 392.39 A39

3-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- propanamide 1.76 378.36A40

1-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- cyclopropanecarboxamide1.77 390.39 A41

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-methyl propanamide 1.79329.39 A42

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-, (2S)- butanamide 1.86329.39 A43

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3-methyl-, (2S)-butanamide1.97 406.42 A44

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3-methyl-, (2R)-butanamide1.97 406.42 A45

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3,3- dimethyl-,(2S)-butanamide 2.09 420.36 A46

2-amino-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4-methyl-, (2S)-pentanamide2.16 420.44 A47

alpha-amino-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-, (alphaS)-benzeneacetamide 2.05 440.32 A48

alpha-amino-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-, (alphaS)-benezenepropanamide 2.23 454.35 A49

alpha-amino-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-, (alphaR)-benezenepropanamide 2.23 454.35 A50

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-, (2R)-2-pyrrolidinecarboxamide 1.82 404.41 A51

N¹-[[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-L- aspartamide 1.67 421.39A52

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-alpha-phenyl-benzeneacetamide 3.17 501.23Alternate Preparation of Example A6

Example A6N-[[3-[1,5-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]trimethylacetamidehydrochloride salt

A6.1:N-[[3-[1,5-dihydro-1-methyl-4-(methyl-t-butyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]trimethylacetamide

A3 (3.0 g, 7.4 mmol) was dissolved in methylene chloride (50 mL).Triethylamine (1.54 mL 11.1 mmol) was added and the mixture cooled in anice bath. Trimethylacetyl chloride (0.78 mL, 9.24 mmol) was addeddropwise and the reaction mixture was stirred for 10 min. Saturatedsodium bicarbonate (3.0 mL) was added, the mixture was stirred for anadditional 5 minutes, and the product was collected by filtration toyield 3.19 g (88%) of A6.1. HPLC YMC S-5 4.6×33 mm (2 min gradient):retention time 1.75 min, M+H⁺=491.41.

A6.2:N-[[3-[1,5-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]trimethylacetamidehydrochloride salt

4N HCl in dioxane (25.0 mL) was added to A6.1 (3.19 g, 6.51 mmol) andthe reaction mixture was stirred at room temperature for 3 hours. Thesolvent was removed under reduced pressure and the product wastriturated with anhydrous ether, filtered and dried under vacuum toprovide 2.76 g (94%) of A6 as a yellow powder. HPLC YMC S-5 4.6×33 mm (2min grad): retention time 1.53 min, M+H⁺=391.46 ¹H NMR (500 MHz) δ 8.27,(s, 1H), 7.59-7.56 (m, 2H), 7.37 (t, J=7 hz, 1H), 7.21 (d, J=7 hz, 1H),7.06 (s, 1H), 4.09 (s, 3H), 3.27 (s, 3H) and 1.21 (s, 9H). ¹³C NMR (400MHz, DMSO) δ 177.8, 144.6, 141.3, 132.8, 131.8, 129.3, 125.6, 123.3,122.7, 98.0, 95.0, 45.7, 42.5, 38.5, 34.0, 28.0, 27.9, 8.9.

Alternate Preparation of Example A17

Example A17N-[[3-[1,5-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-3-methoxypropanamidehydrochloride salt

A17.1:N-[[3-[1,5-dihydro-1-methyl-4-(methyl-tert-butyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-3-methoxypropanamide

EDC (3.21 g, 14.37 mmol) was added in one portion to a mixture of3-methoxypropionic acid (0.91 g, 9.63 mmol), HOBt (1.72 g, 11.01 mmol)and DIPEA (11 mL) in dry acetonitrile (150 mL). After stirring for 20min, A3 (2.10 g, 5.17 mmol) was added and the resulting reactiom mixturewas allowed to stir at room temperature overnight. The reaction mixturewas evaporated in vacuo and the residue was purified by silica gelcolumn chromatography (ethyl acetate) to yield A17.1 (2.1 g, 83%). HPLCYMC S-5 4.6×33 mm (2 min grad): retention time 1.66 min, M+H⁺=493.48

A17.2:N-[[3-[1,5-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl)-3-methoxypropanamidehydrochloride salt

4N HCl in dioxane (25.0 mL) was added to A17.1 (2.0 g, 4.07 mmol) andthe reaction mixture was stirred at room temperature for 2 hours. Thesolvent was removed under reduced pressure and the the product wastriturated with anhydrous ether, filtered and dried under vacuum toprovide 1.5 g (94%) of A17 as a white powder. HPLC YMC S-5 4.6×33 mm (2min grad): retention time 1.36 min, M+H⁺=393.39. ¹H NMR (500 MHz, DMSO)δ 12.14 (s, 1H), 8.95 (br. s, 1H), 8.44-8.41 (m, 1H), 7.74-7.70 (m, 2H),7.40 (t, J=7.6 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H),4.33 (d, J=5.8 Hz, 2H), 4.17 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 3.24 (s,3H), 2.44 (t, J=6.4 Hz, 2H).

Examples A53-A64

Examples A53-A64 was prepared in a manner similar to example A1. Thusintermediate A1.12 was subjected to a what is commonly referred to as aSonoghasira type coupling (as described in detail for the preparation ofA1.13, and conducted in a similar manner) with acetylenes which areeither commercially available, or readily prepared (as described forstep A2.1 and A2.2 and conducted in a similar manner described below).The acetylene were cyclized to the examples in Table A2 in a mannerdescribed in detail in step A1.14. Examples A57 and A58 were resolved bychiral HPLC (Chiralpak AD® 4.6×250 mm, using hexane/methanol/isopropanol84:8:8 with a flow rate of 1 mL/min) starting from racemic A56.

Acetylene Intermediates

For example A56:

A56.1: 1-(3-bromophenyl)ethanamine

A mixture of commercially available 3-bromoacetophenone (30 g, 0.1508mol), formic acid (47 mL) and formamide (70 mL) was heated to 220° C.for 5 h. The brown liquid obtained was cooled to RT, quenched with waterand extracted with ethyl acetate. The organic layer was washed withwater, brine and concentrated. The resulting brown liquid was dissolvedin ethanol (375 mL) and conc. HCl (75 mL) and the mixture was refluxedover night. Ethanol was removed completely and the aqueous layer waswashed with ether and ethyl acetate to remove all non-basic impurities.The aqueous layer was basified with a 10% aqueous sodium hydroxidesolution and extracted with ethyl acetate. The ethyl acetate layer waswashed with brine, and concentrated to provide 26 g (86.65%) of A56.1.This compound was taken to the next step with out further purification.¹H NMR (CDCl₃, 300 MHz) δ 1.38 (d, 3H), 4.1 (q, 1H), 7.2 (m, 1H), 7.27(m, 1H), 7.37 (m, 1H), 7.51 (s, 1H). LS-MS (M−H)⁺=200.

A56.2: tert-butyl 1-(3-bromophenyl)ethylcarbamate

To a solution of A56.1 (15 g, 0.075 mol) in chloroform (150 mL) wasadded di-tert-butyldicarbonate (18 g, 0.0825 mol) slowly at 0° C. andstirred at RT over night. The solvent was removed under vacuum and thecompound was purified by silica gel column chromatography using 5% ethylacetate in petrolium ether as eluent to obtain 20.6 g (94%) of A56.2 aswhite solid. ¹H NMR (CDCl₃, 400 MHz) δ 1.4 (m, 12H), 4.8 (bs, 1H), 7.21(m, 2H), 7.4 (m, 1H), 7.45 (s, 1H). LS-MS (M−H−Boc+CH₃CN)⁺=244.

A56.3: tert-butyl1-(3-(3-hydroxy-3-methylbut-1-ynyl)phenyl)ethylcarbamate

A56.2 (22 g, 0.073 mol) was dissolved in of triethylamine (220 mL) undernitrogen and cuprous iodide (0.695 g, 0.0036 mol) andbis(triphenylphosphine)palladium (II) chloride (1.53 g, 0.0021 mol) wereadded. To this mixture, 2-methyl-3-butyln-2-ol (9.24 g, 0.109 mol) wasadded slowly and heated at 80° C. for 12 h. The reaction mixture wasconcentrated to remove solvents and the residue was dissolved in ethylacetate, washed with water followed by brine. The organic layer wasconcentrated under reduced pressure and the residue purified by silicagel column chromatography using 5% of ethyl acetate in petrolium etherto give 20 g (90%) of A56.3. ¹H NMR (CDCl₃, 400 MHz) δ 1.42 (bs, 12H),1.63 (s, 6H), 4.7 (bs, 1H), 7.29 (m, 3H), 7.36 (s, 1H).

A56.4: tert-butyl 1-(3-ethynylphenyl)ethylcarbamate

A56.3 (20 g, 0.065 mol) was dissolved in isopropyl alcohol and powderedpotassium hydroxide (9.22 g, 0.164 mol) was added. The reaction mixturewas heated to 80° C. for 5 h. The reaction mixture was concentrated andthe residue was dissolved in ethyl acetate, washed with water, brine andconcentrated. The product was purified by column chromatography withpetroleum ether/ethyl acetate mixture to give A56.4, 6.5 g (40%). ¹H NMR(DMSO-d₆, 400 MHz) δ 1.22 (d, 3H), 1.36 (s, 9H), 4.17 (s, 1H), 4.59 (t,1H), 7.32 (m, 3H), 7.40 (s, 1H), 7.45 (s, 1H). LS-MS (M+Na)=268.

For Example A60:

A60.1: (2-(4-chloro-3-methoxyphenyl)ethynyl)trimethylsilane

Commercially available 5-bromo-2-chloroanisole (1.0 g, 4.52 mmol),trimethylsilylacetylene (1.07 mL, 7.5 mmol) and triethylamine (15 mL)were added to anhydrous toluene (15 mL) and degassed by purging withnitrogen. Bis(acetato)bis(triphenylphosphine)palladium II (340 mg, 0.45mmol) was added and the reaction mixture was heated to ˜95° C. for 30min. The reaction mixture was cooled to room temperature, filtered toremove the catalyst, and diluted with ethyl acetate (150 mL). Theorganic layer was washed with saturated sodium bicarbonate (50 mL) andbrine (50 mL) separated, dried over magnesium sulfate, filtered andconcentrated. The residue was purified by flash column chromatographyover silica gel eluted with hexane/ethyl acetate 20:1 to yield A60.1(807 mg, 75%). ¹H NMR (400 MHz): δ 7.40-7.25 (m, 2H), 7.10-7.00 (m, 1H),3.90, (s, 3H), 0.24 (s, 9H).

A60.2: 1-chloro-4-ethynyl-2-methoxybenzene

A60.1 (807 mg, 3.38 mmol) was dissolved in anhydrous THF (35 mL) andcooled in an ice bath. Tetra N-butylammonium fluoride 1 M solution inTHF (4 mL, 4 mmol) was added and the reaction allowed to warm to roomtemperature and stirred for an additional 20 min. The reaction mixturewas concentrated and diluted in 100 mL of ethyl acetate. The organiclayer was washed with water (50 mL) and brine (50 mL), dried overpotassium carbonate, filtered and concentrated under reduced pressure toyield A60.2 (686 mg, 82%). ¹H NMR (400 MHz): δ 7.30-6.90 (complexmultiplet, 3H), 3.80 (s, 3H). TABLE A2

HPLC Retention MS Ex. R Name (min) Reported A53

N,1-dimethyl-7-(3- methylphenyl)-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4-amine,1,6-dihydro- 292.21 1.542 A54

7-(3-chlorophenyl)-1,6- dihydro-N,1-dimethyl- imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine 312.24 1.590 A55

7-(3-fluorophenyl)-1,6- dihydro-N,1-dimethyl- imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine 296.25 1.433 A56

Racemic N-[1-[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]acetamide 363.34 1.333 A57

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]acetamide, Faster elutingEnantiomer A 9.91^(a) A58

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]acetamide, Slower elutingEnantiomer B 13.43^(a) A59

1,6-dihydro-7-(3- methoxyphenyl)-N,1- dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 308.28 1.435 A60

7-(4-chloro-3- methoxyphenyl)-1,6-dihydro- N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 342.27 1.647 A61

1,6-dihydro-N,1-dimethyl-7- [3-(trifluoromethyl)phenyl]-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 346.28 1.682 A62

7-(4-fluorophenyl)-1,6- dihydro-N,1-dimethyl- imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine 296.25 1.415 A63

1,6-dihydro-7-(4- methoxyphenyl)-N,1- dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 308.28 2.380 A64

7-(4-fluorophenyl)-1,6- dihydro-N,1-dimethyl- imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine 312.27 1.557^(a)Chiralpak AD® 4.6 × 250 mm, using hexane/methanol/isopropanol 84:8:8with a flow rate of 1 mL/min.Alternate Preparation of A56 and A57

A56.1a: N-(1-(3-bromophenyl)ethyl)acetamide

A solution of A56.1 (1.0 g, 5 mmol) and triethylamine (576 mg, 5.63mmol) in dichloromethane (30 mL) at 0-5° C. was added acetyl chloride(576 mg, 5.7 mmol) and the reaction mixture was stirred at 0-5° C. for10 minutes, then at room temperature for 10 minutes. The reactionmixture was washed with saturated NaHCO₃ solution (15 ml), water (15ml), then brine (15 ml) and the organic layer dried over magnesiumsulfate. The mixture was filtered and the solution was concentratedunder reduced pressure to yield A56.1a (1.125 g, 93%). HPLC: 68%,retention time: 2.448 minute (condition B). LC/MS (M+H)⁺=244.08, ¹H-NMR(60775-143)

A56.1b: N-(1-(3-ethynylphenyl)ethyl)acetamide

A solution of A56.1a (1.125 g, 4.65 mmol), (trimethylsilyl)acetylene(1.1 ml, 7.7 mmol), Palladium(II)acetate (348 mg, 0.465 mmol) andtriethylamine (15 ml) in toluene (15 ml) was degassed by bubblingnitrogen through the solution then stirred at 95° C. for 30 minutes. Thesolution was filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with ethylacetate to yield the TMS acetylene intermediate. The product wasdissolved in THF (15 ml) at 0-5° C. which was added Bu₄NF (2 ml, 1M inTHF) and the reaction mixture was stirred for 10 minutes. The reactionmixture was concentrated and diluted with EtOAc (50 ml). The organicphase was washed with water (20 ml), brine (20 ml) and the organic layerdried over magnesium sulfate. Filtration and concentration under reducedpressure to yield a crude product which was purified by silica gelcolumn chromatography with Hexanes/EtOAc (3/7 to 100% EtOAc) to yieldA56.1b (345 mg, 40%). HPLC: 71%, retention time: 2.198 minute (conditionB). LC/MS (M+H)⁺=188.15.

A56.1c: tert-butyl7-((3-(1-acetamidoethyl)phenyl)ethynyl)-6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A solution of A1.12 (2.0 g, 4.96 mmol), A56.1b (1.38 g, 7.37 mmol),dichlorobis(triphenylphosphine)palladium(II) (208 mg, 0.296 mmol) andtriethylamine (20 ml) in DMF (14 mL) was degassed by bubbling nitrogenthrough the solvent and was then stirred at 90° C. for 50 minutes. Thereaction mixture was concentrated and diluted with CH₂Cl₂ (200 ml). Theorganic phase was washed with a saturated NaHCO₃ solution (50 ml), thewith brine (50 ml) and the separated organic layer was dried overmagnesium sulfate. The mixture was filtered and the solvent removedunder reduced pressure. The residue was purified on silica gel columnwith EtOAc/MeOH/NH₄OH (200/10/1) to yield A56.1c (844 mg, 37%). HPLC:96%, retention time: 2.753 minute (condition A). LC/MS (M+H)⁺=463.2.

A56.1d:N-[1-[3-[1,6-dihydro-1-methyl-4-(N-methyl-tert-butyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]ethyl]acetamide

A56.1c (844 mg, 1.83 mmol) was dissolved in dimethylacemide (10 ml).Potassium tert-butoxide (2.6 ml, 1M in THF) was added and the reactionmixture was heated at 80° C. for 50 minutes. The reaction mixture wascooled to room temperature, concentrated and the residue purified onsilica gel column with EtOAc/MeOH/NH4OH (200/15/1) to yield A56.1d (648mg, 77%). HPLC: 96%, retention time: 2.572 minute (condition A). LC/MS(M+H)⁺=463.3.

A56.1e: Chiral Separation of A56.1d

Compound A56.1d (100 mg, 0.216 mmol) was subjected to chiral separationto yield A56.1e (29.4 mg, 59%). HPLC: >98%, retention time: 2.565 minute(Condition A). Chiral HPLC: 100% ee. retention time: 9.913 minute(condition D). LC/MS (M+H)⁺=463.3, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.03(1H, s), 7.77 (1H, s), 7.70 (1H, d, J=8.14 Hz), 7.37 (1H, t, J=7.63 Hz),7.24 (1H, d, J=7.63 Hz), 7.19 (1H, s), 5.01 (1H, q, J=6.95 Hz), 4.13(3H, s), 3.32 (3H, s), 1.93 (3H, s), 1.45 (3H, d, J=7.12 Hz), 1.31 (9H,s), 1.08 (3H, d, J=6.10 Hz), and A56.1f (30.1 mg, 60%). HPLC: >98%,retention time: 2.577 minute (condition A). Chiral HPLC: 98.4% ee.retention time: 13.427 minute (condition D). LC/MS (M+H)⁺=463.3, ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.03 (1H, s), 7.77 (1H, s), 7.70 (1H, d, J=8.14Hz), 7.37 (1H, t, J=7.88 Hz), 7.24 (1H, d, J=7.63 Hz), 7.19 (1H, s),5.01 (1H, d, J=7.12 Hz), 4.13 (3H, s), 3.32 (3H, s), 1.93 (3H, s), 1.45(3H, d, J=7.12 Hz), 1.31 (9H, s), 1.08 (3H, d, J=6.10 Hz).

Example A56

A56.1e (29 mg, 0.063 mmol) was dissolved in MeOH (0.5 ml) and 4N HCl indioxane (1 ml) was added. The reaction mixture was heated at 50° C. for90 minutes. The mixture was cooled to RT and Et₂O (2 ml) was added andthe resulting mixture stirred for 10 minutes. The solid was collectedand dried to provide A56 (23.7 mg, 95%). HPLC: >98%, retention time:1.957 minute (Condition A). Chiral HPLC: >98% ee. retention time: 5.25minute (condition E). LC/MS (M+H)⁺=363.3, ¹H-NMR (400 MHz, CD₃OD) δ ppm8.12 (1H, s), 7.61 (1H, s), 7.55 (1H, d, J=7.63 Hz), 7.35 (1H, t, J=7.88Hz), 7.23 (1H, d, J=7.63 Hz), 4.92-5.00 (1H, m), 4.08 (3H, s), 3.18 (3H,s), 1.90 (3H, s), 1.41 (3H, d, J=7.12 Hz).

A57

A56.1f (30 mg, 0.065 mmol) was dissolved in MeOH (0.5 ml) and 4N HCl indioxane (1 ml) was added. The reaction mixture was heated at 50° C. for90 minutes. The reaction mixture was cooled to RT and Et₂O (2 ml) wasadded. The reaction mixture was stirred for 10 minutes. The solid wascollected and dried to provide A57 (23.1 mg, 89%). HPLC: >98%, retentiontime: 1.975 minute (Condition A). Chiral HPLC: 92% ee. retention time:7.26 minute (condition E). LC/MS (M+H)⁺=363.3, ¹H-NMR (400 MHz, CD₃OD) δppm 7.61 (1H, s), 7.55 (1H, d, J=7.63 Hz), 7.35 (1H, t, J=7.88 Hz), 7.23(1H, d, J=7.63 Hz), 7.10 (1H, s), 6.06 (1H, s), 4.96 (1H, d, J=7.12 Hz),4.08 (3H, s), 3.18 (3H, s), 1.90 (3H, s), 1.41 (3H, d, J=7.12 Hz).

Example A65 1,6-dihydro-1-methyl-4-(methylamino)-7-phenyl-methyl esterimidazo[4,5-d]pyrrolo[2,3-b]pyridine-8-carboxylic acid

A1.13 (97 mg, 0.26 mmol), sodium acetate (70 mg, 0.51 mmol), potassiumcarbonate (71 mg, 0.50 mmol) and copper (II) chloride dihydrate (131 mg,0.77 mmol) were added to anhydrous methanol (6.5 mL) and degassed bypurging with nitrogen. Palladium chloride (5.3 mg, 0.03 mmol) was addedand the reaction was placed in a stainless steel bomb and pressurized to20 psi with carbon monoxide. The reaction was heated to 60° C. for 16 h.The reaction was allowed to cool to room temperature, evacuated toremove carbon monoxide and brought to atmospheric pressure by theaddition of air. The solvent was removed under reduced pressure. Theresidue was treated with saturated ammonium chloride solution (5 mL) andconcentrated ammonium hydroxide (5 mL), and extracted with chloroform(3×25 mL). The combined organic layers were dried over magnesiumsulfate, filtered and concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC to yield 1,6-dihydro-N,1-dimethyl-N-t-butyloxycarbonyl-7-phenylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine. The BOC protected productwas dissolved in trifluoroacetic acid (2 mL) stirred for 20 minutes andconcentrated under reduced pressure to yield A65 (42 mg, 37%).M+H+=336.26. ¹H NMR (400 MHz) MEOD δ 8.15 (s, 1H), 7.66 (t, J=2.5 Hz,2H), 7.46 (s, 3H), 4.24 (s, 1.5H), 3.92 (s, 1.5H), 3.29 (s, 3H).

Example A66N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]urea

A3.1 (21 mg, 0.05 mmol) was dissolved in dichloromethane (1 mL).Trimethylsilylisocyanate (13.5 μL, 0.1 mmol) was added and the reactionmixture heated to 60° C. for 30 minutes. The reaction mixture wasallowed to cool to room temperature then trifluoroacetic acid (0.5 mL)was added and the mixture was stirred for 0.5 h. The solvent was removedunder reduced pressure and the product purified by preparatory reversephase HPLC to yield A66 (7.8 mg, 33%). M+H+=350.35. ¹H NMR (400 MHz)DMSO δ 11.90 (s, 1H), 8.20 (s, 1H). 7.8-7.70 (m, 2H), 7.40-7.30 (t, 1H),7.18-7.08 (m, 2H), 6.43 (br s, 1H), 4.20 (d, 2H), 4.09 (s, 3H), 3.05 (s,3H).

Example A67N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]guanidine

A3.1 (21 mg, 0.05 mmol), and1,3-bis(t-butoxycarbonyl)-1-methyl-2-thiopseudourea were dissolved inDMF (0.5 mL). Triethylamine (21 μL, 0.053 mmol) and mercuric chloride(15 mg, 0.055 mmol) were added and the reaction mixture allowed to stirat room temperature for 16 h. The reaction mixture was diluted with 10mL of ethyl acetate. The solids were removed by filtration and thefiltrate evaporated under reduced pressure. The residue was purified onpreparatory reverse phase HPLC to yield the boc-protected intermediateN-[[3-[1,6-dihydro-1-methyl-4-(N-tbutyloxycarbonyl-N-methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]guanidine.The solid was dissolved in methylene chloride (0.5 mL). Trifluoroaceticacid (0.5 mL) was added and the reaction mixture stirred for 0.5 h. Thesolvent was evaporated under reduced pressure to provide A67 (17 mg,59%). M+H+=349.34. ¹H NMR (400 MHz) MEOD δ 8.2 (s, 1H), 7.82-7.78 (m,2H), 7.50 (t, 1H), 7.3 (d, 1H), 7.22 (s, 1H), 4.51 (s, 2H), 4.18 (s,3H). 3.33 (s, 3H).

Example A687-[3-(aminomethyl)phenyl]-1,6-dihydro-1-methyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A68.1:N-(4-methoxybenzyl)-6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-4-amine

A1.5 (17.6 g, 87.6 mmol) and paramethoxybenzyl amine (40 mL) were heatedat 110° C. for 4 hours. The reaction mixture was cooled to roomtemperature and quenched with water. The product precipitated and wascollected by filtration and air dried to yield A68.1 (24.6 g, 93%)M+H+=305.25, 305.24.

A68.2: tert-butyl4-methoxybenzyl(6-chloro-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate

A68.1 (5.0 g, 16.6 mmol) was dissolved in THF (300 mL) and cooled to−78° C. Sodium bis(trimethylsilyl)amide 1M in THF (21 mL, 21 mmol) wasadded over 2 min and allowed to stir at −78° C. for 25 min.Ditertbutyldicarbonate (4.0 g, 18.3 mmol) was added and the reactionmixture was allowed to warm to room temperature and stirred overnight.The solvent was removed under reduced pressure and the residuepartitioned between ethyl acetate and water. The organic layer waswashed twice with water, separated, dried over magnesium sulfate,filtered and evaporated under reduced pressure. The crude product waspurified by flash silica gel column chromatography (ethyl acetate/hexane(1:1) to 100% ethyl acetate) to yield A68.2 (6.4 g, 96%). LCMS: rettime=1.83 min., M+H⁺=303.23

A68.3: tert-butyl4-methoxybenzyl(6-(diphenylmethyleneamino)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate

A68.2 (6.4 g, 15.9 mmol), benzophenone imine (3.45 g, 19.1 mmol),tris(dibenzylidineacetone)dipalladium (0) (292 mg, 0.32 mmol),Xanthphos® (276 mg 0.48 mmool) and desium carbonate (7.24 g, 22.3 mmol)were added to anhydrous 1,4-dioxane (40 mL). The reaction mixture washeated at 90° C. overnight, allowed to cool to room temperature and thesolvent removed under reduced pressure. The residue was partitionedbetween water and ethyl acetate, and the organic layer was washed twicewith water. The organic layer was separated, dried over magnesiumsulfate, filtered and the solvent removed under reduced pressure. Theresidue was purified by flash silica gel column chromatography (ethylacetate/hexane (1:1) to 100% ethyl acetate) to yield A68.3 (6.78 g,78%). Electrospray MS: M+H⁺=548.20.

A68.4: tert-butyl4-methoxybenzyl(6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate

A68.3 (100 mg, 0.18 mmol) was dissolved in anhydrous THF (0.6 mL) andaqueous 1 M HCl (0.4 mL) was added and the reaction mixture was stirredfor 2 min. 1 M NaOH (0.8 mL) was added and the reaction mixture wasextracted with ethyl acetate. The organic layer was separated, driedover magnesium sulfate, filtered and the solvent removed under reducedpressure. The residue was dried under vacuum for ˜1 h and trituratedfour times with diethyl ether. The residue was dried under vacuum toyield A68.4 (42 mg, 60%). LCMS: ret time=1.48 min., M+H⁺=384.28, 284.23(100%, M+H+−Boc). The reaction was repeated on a larger scale usingessentially the same procedure. Thus A68.3 (7.18 g, 13.1 mmol) reactedin a similar manner to that described above yielded A68.4 (4.09 g, 81%).

A68.5: tert-butyl4-methoxybenzyl(6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate

A68.4 (4.07 g, 10.6 mmol) was dissolved in anhydrous acetonitrile (200mL) and N-iodosuccinimide (2.65 g, 11.3 mmol) was added in one portion.The reaction mixture was stirred for 0.5 h, at which point additionalN-iodosuccinimide (200 mg) was added the reaction was stirred for anadditional 0.5 h at which point a second addition of N-iodosuccinimide(200 mg) was added and the reaction and stirred for an additional 0.5 h.The solvent was evaporated and the residue was purified by flash silicagel column chromatography, ethyl acetate/hexane 1:1 to ethylacetate/hexane 2:1, to yield A68.5 (3.72 g, 69%). ElectrosprayM+H⁺=510.02.

A68.6: tert-butyl4-methoxybenzyl(6-amino-7-(2-(3-cyanophenyl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate

A68.5 (11.0 g, 1.96 mmol), and A2.2 (0.5 g, 3.93 mmol), were added to amixture of triethylamine (9 mL) and N,N-dimethylformamide (7 mL) andnitrogen bubbled through the mixture.Dichlorobis(triphenylphosphine)palladium (84 mg, 0.12 mmol) was addedand the reaction was heated at 90° C. for 4 h. The mixture was allowedto cool to room temperature and the volatiles removed under reducedpressure. The residue was purified by flash silica gel columnchromatography eluting with hexane/ethyl acetate 1:1 to yield A68.6 (647mg, 65%). LCMS: ret time=1.74 min., M+H⁺=509.31, 409.28 (100%,M+H+−Boc).

A68.7:3-[1,6-dihydro-1-methyl-4-(N-tert-butyloxycarbonyl-N-(4-methoxyphenylmethyl)amino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]benzonitrile

Potassium t-butoxide (172 mg, 1.54 mmol) was dissolved in DMSO (9 mL).A68.6 (623 mg, 1.23 mmol) was dissolved in DMSO (9 ML) and addeddropwise to the potassium tert-butoxide solution. After the addition wascomplete the reaction mixture was heated to 80° C. for 3 h. Additionalpotassium t-butoxide (100 mg) was added and the reaction heated for anadditional 10 min. At which point TLC indicated complete consumption ofA68.6. The reaction mixture was allowed to cool to room temperature anddiluted with water. The precipitate was filtered under vacuum overnight,during which time the filtrate had evaporated. The filter cake waswashed into the filter flask by addition of methanol and the solutioncollected and evaporated under reduced pressure. The residue waspurified by flash silica gel column chromatography eluting withhexane/ethyl acetate 1:1 to yield A68.7 (350 mg, 56%). LCMS: rettime=1.75 min., M+H⁺=509.31, 409.28 (100%, M+H+−Boc). ¹H NMR 400 mHz,CDCl₃ δ 9.52 (br s, 1H), 7.90, (s, 1H), 7.78-7.72 (m, 1H) 7.66 (s, 1H),7.60-7.50 (m, 2H), 7.44 (apparent d, 2H), 6.92 (s, 1H), 6.72 (apparentd, 2H).

A68.8:3-[1,6-dihydro-1-methyl-4-(N-tert-butyloxycarbonyl-N-(4-methoxyphenylmethyl)amino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]benzylamine

A68.7 (30 mg, 0.06 mmol) was dissolved in 95% ethanol (2 mL). A portionof Raney nickel was washed with ethanol (20 mL). A small spatula fullwas added and the reaction mixture saturated with ammonia (gas) and aballoon of hydrogen was attached to the reaction vessel. The reactionwas complete after 2 h. The mixture was filtered though celite andevaporated under reduced pressure to yield A68.8 (46 mg, 150%). LCMS rettime=1.49 min., M+H⁺=513.25, 413.26 (100%, M+H+−Boc). The material wasused without further purification in the next step.

A68.9:7-[3-(aminomethyl)phenyl]-1,6-dihydro-1-methyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A68.8 (46 mg from above) was dissolved in a mixture of trifluoroaceticacid and methylene chloride (1:1, 5 mL) and allowed to stir at roomtemperature in an open flask overnight. The solvent was evaporated underreduced pressure and dried under vacuum, and the residue was taken up indiethyl ether, which provided a tan solid (40 mg). The solid was takenup in methanol and silica gel was added and the solvent removed underreduced pressure. The silica gel from above was placed on top ofadditional silica gel and the product eluted with a mixture of methylenechloride/methanol/conc. ammonium hydroxide (100:10:1) to provide 13.3 mg(76% over two steps). LCMS: ret time=0.95 min., M+H⁺=293.21.

Example A69N-[[3-(4-Amino-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]methyl]acetamide,trifluoroacetate salt

Acetic acid (5 mg, 0.073 mmol), HOBT (15 mg, 0.10 mmol), anddiisopropylethylamine (0.1 mL, 0.70 mmol) were added to anhydrousacetonitrile (1 mL). EDC (28 mg, 0.14 mmol) was added and the reactionmixture stirred for 5 minutes. A68.8 (30 mg, 0.058 mmol) was added andthe reaction mixture stirred over the weekend. The volatiles wereremoved under reduced pressure and trifluoroacetic acid (1 mL) was addedand the reaction mixture was stirred at room temperature for 4 hours.The solvent was evaporated and the residue purified by preparatoryreverse phase column chromatography to yield A69 as the trifluoroacetatesalt (16.4 mg, 63%). LCMS: ret time=1.1 min., M+H⁺=335.29. ¹H NMR 400mHz, MeOD δ: 8.15 (s, 1H), 7.76-7.68 (m, 2H), 7.70 (t, J=7.7 Hz, 1H),7.29 (d, J=7.7 Hz, 1H), 7.20 (s, 1H), 4.49 (s, 22H), 4.16 (s, 3H), 2.04(s, 3H).

Example A707-(3-Fluorophenyl)-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A70.1: tert-Butyl4-methoxybenzyl(6-amino-7-(2-(3-fluorophenyl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)carbamate

A68.5 (2.0 g, 3.9 mmol) and 3-fluorophenyl acetylene (0.95 g, 7.86 mmol)were dissolved in a mixture of triethylamine (18 mL) and methylenechloride (20 mL) and degassed by passing nitrogen through the solution.Dichlorobis(triphenylphosphine)palladium (200 mg 0.2 mmol) was added andthe reaction was heated at 70° C. overnight. The volatiles were removedunder reduced pressure and the residue was purified by flash silica gelcolumn chromatography eluting with hexane/ethyl acetate 1:1 to yieldA70.1 (1.61 g, 81%). LCMS ret time=1.86 min., M+H⁺=504.32, 404.32 (100%,M+H+−Boc). ¹H NMR 400 mHz, CDCl₃ δ: 8.30-8.10 (br s, 2H), 7.60 (s, 1H),7.38-7.26 (m, 4H), 7.26 (d, 1H), 7.08 (t, 1H), 7.66 (d, 2H), 5.04 (s,2H), 4.04 (s, 3H), 3.74 (s, 3H), 1.40 (s, 9H).

A70.2:7-(3-Fluorophenyl)-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-(N-(4-methoxyphenylmethyl)-N-tert-butyloxycarbonylamine

A70.1 (1.61 g, 3.22 mmol) was prepared in a manner similar to thatdescribed in step A68.7 to provide A70.2 (0.75 g, 47%). LCMS rettime=1.88 min, M+H⁺=502.24, 402.24 (100%, M+H+−Boc).

A70.3:7-(3-Fluorophenyl)-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

Trifluoroacetic acid (1.2 mL) was added to a mixture of A70.2 (100 mg,0.20 mmol) and anisole (0.43 mL). The reaction was stirred overnight atroom temperature. The volatiles were removed under reduced pressure andthe solid triturated with diethyl ether. The solid was recrystallizedfrom methanol to yield A70 (11 mg, 20%) as the trifluoroacetate salt.LCMS ret time=1.39 min., M+H⁺=282.23, ¹H NMR 500 mHz, CD₃OD δ: 8.09 (s,1H), 7.56 (d, 1H), 7.48 (d, 1H), 7.42 (t, 1H), 7.21 (s, 1H), 7.02 (t,1H), 4.10 (s, 3H).

Example A718-chloro-7-(3-fluorophenyl)-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine,trifluoroacetate salt

A71.1:7-(3-Fluorophenyl)-1,6-dihydro-1-methyl-8-chloro-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-(N-(4-methoxyphenylmethyl)-N-tert-butyloxycarbonylamine

A70.2 (100 mg, 0.20 mmol) and N-chlorosuccinimide (27 mg, 0.2 mmol) weredissolved in anhydrous acetonitrile and heated to 100° C. in a sealedvial for 30 min. The reaction mixture was allowed to cool to roomtemperature during which time the product precipitated. A71.1 (57 mg,53%) was collected as a white solid. LCMS ret time=1.98 min M+H⁺=536.27,436.27 (100%, M+H+−Boc). ¹H NMR 500 mHz, CD₃OD δ: 8.06 (s, 1H). 7.68 (d,J=8 Hz, 1H), 7.65 (d, J=9 Hz, 1H), 7.54-7.46 (m, apparent d of d, 1H),7.27 (d, J=9 Hz, 2H), 7.18-7.12 (m, apparent t, 1H), 6.72 (d, J=8 Hz,2H), 5.02 (s, 2H), 4.30 (s, 3H), 3.68 (s, 3H), 1.36 (s, 9H).

A71.2:8-chloro-7-(3-fluorophenyl)-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-aminetrifluoroacetate salt

Trifluoroacetic acid (1 mL) was added to a mixture of A71.1 (57 mg, 0.11mmol) and anisole (0.25 mL) and stirred at room temperature overnight.The volatiles were removed under reduced pressure and the solidtriturated with diethyl ether and dried to yield A71 (40 mg, 87%). LCMSret time=1.70 min, M+H+=316.15

Example A723-(1-Methyl-4-methylamino-1,6-dihydro-1,3,5,6-tetraaza-as-indacen-7-yl)-benzoicacid

A72.1:3-[6-Amino-4-(tert-butoxycarbonyl-methyl-amino)-1-methyl-1H-imidazo[4,5-c]pyridin-7-ylethynyl]-benzoicacid tert-butyl ester

Dichlorobis(triphenylphosphine)palladium (104 mg, 0.145 mmol) was addedin one portion to a mixture of A1.12 (1.0 g, 2.48 mmol),3-ethynyl-benzoic acid tert-butyl ester (753 mg, 3.72 mmol) andtriethylamine (10 ml) in DMF (7.0 ml) at room temperature under anitrogen atmosphere. The resulting mixture was heated to 90° C. for 50min before cooling to room temperature and evaporating in vacuo. Theresidue was purified by column chromatography using ethyl acetate:hexaneas eluent to give 765 mg (65%) of A72.1. Found: M+H=478.21

A72:3-(1-Methyl-4-methylamino-1,6-dihydro-1,3,5,6-tetraaza-as-indacen-7-yl)-benzoicacid

Potssium tert-butoxide (1M in THF, 1.70 ml, 1.70 mmol) was addeddropwise to a solution of A72.1 (765.0 mg, 1.60 mmol) in DMA (8.0 ml)under a nitrogen atmosphere. The resulting mixture was heated to 80 Cfor 20 min before cooling to room temperature, and evaporating in vacuo.The residue was immediately dissolved in TFA and allowed to stir at roomtemperature for 16 hrs before evaporating in vacuo. MeOH was added tothe residue and the mixture stirred at RT for 5 min before collectingthe precipitated solid by vacuum filtatrion to provide A72 (210 mg). Aportion (15 mg) of this material was further purified by preparativeHPLC to provide A72 (3.0 mg) as an off-white solid. LC/MS Phenomenex S54.6×30 mm (2 min gradient) Found: M+H⁺=322.26 at 1.387 min.

Example A73N-Cyclopropyl-3-(1-methyl-4-methylamino-1,6-dihydro-1,3,5,6-tetraaza-as-indacen-7-yl)-benzamide

BOP-Cl (85 mg, 0.336 mmol) was added in one portion to a solution of A72(18.0 mg, 0.056 mmol), cyclopropylamine (7.76 μL, 0.112 mmol) andtriethylamine (47 μL, 0.336 mmol) in DMF (0.5 ml) at 0 C under anitrogen atmosphere. The resulting mixture was warmed to roomtemperature and stirred for 25 min before evaporating in vacuo andpurifying by preparative HPLC to provide A73 (4.0 mg) as an off-whitesolid. LC/MS Phenomenex S5 4.6×30 mm (2 min gradient) Found: M+H⁺=361.34at 1.370 min.

Example A74[3-(1-Methyl-4-methylamino-1,6-dihydro-1,3,5,6-tetraaza-as-indacen-7-yl)-phenyl]-morpholin-4-yl-methanone

BOP-Cl (85 mg, 0.336 mmol) was added in one portion to a solution of A72(18.0 mg, 0.056 mmol), morpholine (9.8 μL, 0.112 mmol) and triethylamine(47 μL, 0.336 mmol) in DMF (0.5 ml) at 0 C under a nitrogen atmosphere.The resulting mixture was warmed to room temperature and stirred for 25min before evaporating in vacuo and purifying by preparative HPLC toprovide A74 (10.4.0 mg) as an off-white solid. LC/MS Phenomenex S54.6×30 mm (2 min gradient) Found: M+H⁺=391.25 at 1.295 min.

Example A757-(3-bromophenyl)-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A75.1: tert-Butyl6-amino-1-methyl-7-(2-(3-bromophenyl)ethynyl)-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A1.12 (201 mg, 0.5 mmol), bis(triphenylphosphine)palladium dichloride(21 mg, 0.03 mmol), 3-bromophenylacetylene (113 mg, 0.65 mmol) copperiodide (4.3 mg, 0.025 mmol) and diisopropylethylamine (0.2 mL 1.5 mmol)were suspended in DMF (2.5 mL) and degassed by bubbling a stream ofnitrogen through the reaction for several minutes. The reaction was thenheated to 75° C. for 30 minutes and was concentrated and purified bysilica gel chromatography (hexane/ethylacetate gradient) to yield A75.1.(281 mg 123%) LCMS: RT=3.47 min M+H+=458.19. The material was used inthe next step without further purification.

A75.2:7-(3-bromophenyl)-1,6-dihydro-N,1-dimethyl-1-(tertbutyloxycarbonyl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A75.1 (281 mg, 0.61 mmol) and potassium tert-butoxide (1 Molar solutionin THF, 900 μL, 0.90 mmol) were dissolved in DMA (2.8 mL) and heated at70° C. for 10 minutes. The reaction mixture was concentrated andpurified by silica gel chromatography (hexane/ethyl acetate gradient) toyield A75.2 (154 mg, 54%). LCMS RT=3.4 min, M+H⁺=458.19.

A75.3:7-(3-bromophenyl)-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A75.2 (21 mg, 46 mmol) was dissolved in a mixture of 4N HCl in dioxane(1 mL) and ethanol (1 mL). The reaction mixture was stirred at roomtemperature for 16 h then at 40° C. for 3 h. The solvent was evaportedand the solid collected to yield A75 (6.6 mg, 40%) as the hydrochloridesalt. M+H⁺=356.16. ¹H NMR (400 MHz, CD₃OD) δ ppm 8.13 (1H, s), 7.87 (1H,t, J=1.78 Hz), 7.65 (1H, d, J=8.65 Hz), 7.38 (1H, d, J=8.65 Hz), 7.28(1H, t, J=7.88 Hz), 7.16 (1H, s), 4.06 (3H, s), 3.18 (3H, s)

Example A763-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-benzoicacid, ethyl ester

A75.2 (21 mg, 0.046 mmol), palladium acetate (2.25 mg, 0.01 mmol), and1,3-bis(diphenylphosphino)propane (4.13 mg, 0.01 mmol) were dissolved inethanol (˜1 mL) and potassium carbonate (19 mg, 0.14 mmol) was added.The reaction mixture was placed in a sealed microwave vial and blankedwith carbon monoxide. The reaction mixture was heated in a microwaveapparatus for 15 minutes at 100° C. The solvent was evaporated and theresidue purified on preparatory HPLC to yield the BOC protected product.The BOC protected product was dissolved in a small amount oftrifluoroacetic acid and stirred at room temperature for 20 min, andconcentrated to yield the crude product which was purified bypreparatory thin layer chromatography (methylene chloride methanol,ammonium hydroxide 100:5:1. The appropriate band was collected andwashed from the silica gel with additional solvent and evaporated toyield A76 (3.8 mg, 23%). LCMS RT=2.55 min, M+H+=350.29. NMR 400 MHzD₃COD: δ 8.3 s, 1H, 8.0-7.7 m, 2H, 7.4-7.2, m, 2H, 7.0 s, 1H, 4.3 q, 2H,4.0 s, 1H, 3.0, s, 1H, 1.34 t, 3H. TABLE A2

HPLC Retention MS Ex. R Name (min) Reported A77

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-(2-furanylmethyl)- benzamide 2.61401.45 A78

(2S)-1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-2- pyrrolidinecarboxamide 2.11418.44 A79

1-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-3-pyrrolidinol 2.04 391.46 A80

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-[(tetrahydro-2-furanyl)methyl]-benzamide 2.47 405.48 A81

4-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-thiomorpholine 2.58 407.42 A82

1-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-piperidine 2.72 389.48 A83

1-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-3- piperidinecarboxamide 2.14432.44 A84

1-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-4-piperidinol 2.06 405.45 A85

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-(3-pyridinylmethyl)- benzamide 1.93412.42 A86

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-[2-(1-piperidinyl)ethyl]- benzamide2.02 432.48 A87

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-(2-methylpropyl)- benzamide 2.8 377.48A88

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-ethyl-benzamide 2.36 349.47 A89

N-[2-(acetylamino)ethyl]-3- [1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]- benzamide 2.12406.46 A90

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-(4-hydroxybutyl)- benzamide 2.25 393.47A91

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N,N-diethyl-benzamide 2.59 377.48 A92

3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- N-methyl-N-propyl benzamide 2.64 377.49A93

N-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-glycine, ethyl ester 2.45 407.43A94

N-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-beta-alanine, ethyl ester 2.56421.44 A95

4-[[3-[1,6-dihydro-1-methyl- 4-(methylammo)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]amino]-butanoic acid, ethyl ester2.69 435.44 A96

1-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-4- piperidinecarboxamide 1.99432.44 A97

1-acetyl-4-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-piperazine 2.04 432.42 A98

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-3-pyrrolidinyl]- acetamide 2.06432.43 A99

1-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-4- piperidinemethanol 2.20 419.47A100

4-[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]benzoyl]-2-piperazinone 1.85 404.42

Example A1013-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-benzoicacid, methyl ester

A101.1: 3-Bromo-5-fluorobenzoic acid methyl ester

Commercially available 3-bromo-5-fluorobenzoic acid (1.0 g, 4.57 mmol)was dissolved in methylene chloride (20 mL) trimethylsilyl diazomethane(2M solution in hexane) (5 mL, 10 mmol) was added and the reactionmixture was stirred for 30 min. at room temperature. The reactionmixture was concentrated and purified by silica gel chromatography(hexane/methylene chloride 2:1) to yield A101.1 (229 mg, 21%).

A101.2: 3-Fluoro-5-(trimethylsilylethynyl)benzoic acid methyl ester

A101.1 (229 mg, 0.98 mmol), bis-(triphenylphosphine)palladium diacetate(75 mg, 0.1 mmol), and triethylamine (2.8 mL) were added to toluene (2.8mL) and degassed by bubbling nitrogen through the solution for a fewminutes. Trimethylsilylacetylene (225 μL, 1.6 mmol) was added and thereaction mixture heated to 95° C. for 30 min. The reaction mixture wascooled to room temperature and concentrated under reduced pressure toyield a dark oil which was purified on silica gel chromatography(hexane/methylene chloride 2:1) to yield A101.2 (162 mg, 66%).

A101:3: 3-Ethynyl-5-fluorobenzoic acid methyl ester

A101.2 (162 mg, 0.64 mmol) was added to a solution of aqueous potassiumhydroxide (using an aliquot of 5.1 μL of a 200 mg KOH/2 mL watersolution) in methanol (1.2 mL) and stirred for 30 min. The mixture wasconcentrated to yield a dark oil. The product was purified by silica gelchromatography (hexane/dichloromethane 2:1) to yield A101.3 (107 mg,93%) LCMS: Ret. Time=3.46 min, M+H⁺=179.16

A101.4:3-((6-amino-4-(tert-butyloxycarbonyl(methyl)amino)-1-methyl-1H-imidazo[4,5-c]pyridine-7-yl)ethynyl)-5-fluorobenzoicacid, methyl ester

A101.3 (107 mg, 0.6 mmol), A1.12 (164 mg, 0.41 mmol)bis(triphenylphophine)palladium dichloride and triethylamine weredegassed by bubbling nitrogen through the reaction for several minutesand then heated under a nitrogen atmosphere at 90° C. for 30 minutes.The mixture was concentrated under reduced pressure and the productpurified by silica gel chromatography (hexane/ethyl acetate) to yieldA101.4 (148 mg, 80%). LCMS: Ret. Time=3.53 min, M+H⁺=454.39.

A101.5:3-((4-tert-butyloxycarbonyl(methyl)amino)-1-methyl-6-(2,2,2-trifluoroacetamido)-1H-imidazo[4,5-c]pyridin-7-yl)ethynyl-5-fluorobenzoicacid methyl ester

A101.4 (148 mg, 0.33 mmol) was dissolved in a mixture of triethylamine(150 μL) in methylene chloride and cooled in a bath maintained between0° C. and 5° C. Trifluoroacetic anhydride (140 μL, 1.0 mmol) and allowedto warm up to room temperature. The reaction mixture was stirred for anadditional 20 minutes and then diluted methylene chloride (10 mL) andwashed with saturated sodium bicarbonate (5 mL) followed by brine (5mL). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to yield a brown oil. The productwas purified by silica gel chromatography (hexane/ethyl acetate 2:3) toyield A101.5 (92.5 mg, 52%). LCMS: ret. Time=3.66 min. M+H⁺=550.34.

A101.6:3-[1,6-dihydro-1-methyl-4-((methyl)tertbutoxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-benzoicacid methyl ester

A101.5 (72 mg, 0.036 mmol), potassium carbonate (20 mg) andtetrakis(triphenylphosphine)palladium (0) (9.1 mg) were dissolved in DMA(1.5 mL). The reaction mixture was heated in a microwave apparatus for45 min at 130° C. The reaction mixture was concentrated under reducedpressure and the residue purified by silica gel chromatography(hexane/ethyl acetate) to yield A101.6 (66 mg, 87%). LCMS: ret time=3.48min, M+H⁺=454.25.

A101.7:3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-benzoicacid, methyl ester trifluoacetate salt

A101.6 (10 mg) was dissolved in a mixture of trifluoroacetic acid (0.25mL) and methylene chloride (0.25 mL) and stirred at room temperature for15 min. The reaction mixture was concentrated under reduced pressure theresidue was diluted with methanol (0.25 mL) and stirred for 10 min. Theproduct was filtered and dried to yield A101 (6 mg, 58%) LCMS: rettime=2.67 min, M+H+=354.31

Example A1023-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-benzoicacid

A102.1:3-[1,6-dihydro-1-methyl-4-((methyl)tert-butyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-benzoicacid

A101.6 (54 mg, 0.12 mmol) was dissolved in a mixture of 1N sodiumhydroxide (0.3 mL) and methanol (2.5 mL) and heated in a microwaveapparatus at 100° C. for 15 min. The reaction mixture was concentratedunder reduced pressure and diluted with water (1 mL). 1N HCl was addeduntil the pH was between 1 and 2 (pH paper). The solid was collected byfiltration and dried to yield A102.1 (42 mg, 80%). LCMS: ret time=3.17min, M+H⁺=440.32.

A102.2:3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-benzoicacid, trifluoro acetate salt

A102.1 (10 mg, 0.022 mmol) was dissolved in a mixture of trifluoroaceticacid (0.25 mL) and methylene chloride (0.25 mL) and stirred at roomtemperature for 20 min. The reaction mixture was concentrated underreduced pressure. The residue was diluted with methanol (0.5 mL) andstirred for 5 min. The solid was filtered and dried to yield A102 (5 mg,65%) LCMS: ret time=2.42 min, M+H⁺=340.33

Example A1034-[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorobenzoyl]-morpholine,trifluoacetate salt

A102.1 (16 mg, 0.036 mmol), morpholine (3.5 μL, 0.04 mmol) andtriethylamine (47 μL. 10.3 mmol) were dissolved in DMF in a bathmaintained between 0° C. and 5° C. BOP-Cl (85 mg, 0.34 mmol) was addedand the reaction allowed to warm to room temperature and stirred for 30min. The reaction mixture was concentrated under reduced pressure andthe residue purified by preparatory reverse phase HPLC to yield the BOCprotected derivative (LCMS ret time=2.84 min, M+H⁺=509.32). Theintermediate was stirred in a mixture of dichloromethane (0.25 mL) andtrifluoroacetic acid (0.25 mL) for 10 minutes and concentrated to yieldA103 (9.8 mg, 51%) LCMS: ret time=2.06 min, M+H⁺=409.35.

Example A1043-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-N-(2-methoxyethyl)-benzamide,trifluoroacetate salt

A102.1 (16 mg, 0.036 mmol), HOBT (8.7 mg, 0.64 mmol), anddiisoproplyethylamine (76 μL) was dissolved in acetonitrile. EDCI (16.5mg, 0.086 mmol) was added and the reaction mixture stirred for 5 min. atroom temperature. 2-Methoxyethylamine (4 μL, 0.39 mmol) was added andthe reaction mixture stirred for 30 minutes at room temperature followedby 30 minutes at 80° C. The reaction mixture was concentrated underreduced pressure and purified by preparatory reverse phase HPLC to yieldthe BOC protected derivative (M+H⁺=497.28). The intermediate wasdissolved in dichloromethane (0.25 mL) and trifluoroacetic acid (0.25mL), stirred at room temperature for 10 min and concentrated underreduced pressure to yield a clear oil. The residue was washed withdiethyl ether and dried under vacuum overnight to yield A104 (14.5 mg78%). LCMS: ret time=2.26 min, M+H+=397.33

Examples A105-A130 A105a:[7-[4-(aminomethyl)phenyl]-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl]methyl-carbamicacid, 1,1-dimethylethyl ester

A105a.1: tert-Butyl6-amino-7-(2-(4-cyanophenyl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A1.12 (1.0 g, 2.48 mmol), dichlorobis(triphenylphosphine)palladium (24mg, 0.12 mmol), 4-ethynylbenzonitrile (631 mg, 4.96 mmol) andtriethylamine (0.7 mL, 5.0 mmol) were each added toN,N-dimethylformamide (10 mL) and nitrogen bubbled through the resultingmixture for 5 min. The reaction mixture was heated at 90° C. for 20 minunder a nitrogen atmosphere before cooling to room temperature andevaporating the solvent in vacuo. The residue was purified by silica gelcolumn chromatography using ethyl acetate as eluent to provide 0.58 g(60%) of A105a.1. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time1.69 min, M+H⁺=403.35.

A105a.2:4-[1,5-Dihydro-1-methyl-4-(N-tert-butyloxycarbonyl-N-methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]benzonitrile

A105a.1 (0.55 g, 1.37 mmol) was dissolved in dimethylacetamide (7 mL).Potassium t-butoxide, 1M in THF (2.10 ml, 2.10 mmol) was added and thereaction heated in an oil bath maintained at 80° C. for 20 min. Thereaction was allowed to cool to room temperature and the solvent wasremoved under reduced pressure. The residue was purified by silica gelcolumn chromatography using ethyl acetate as the eluent to yield 0.73 g(78%) of A105a.2 HPLC YMC S-54.6×33 mm (2 min grad): retention time 1.38min, M+H⁺=403.31. ¹H NMR (400 MHz, MeOD) δ 8.02 (s, 1H), 7.95 (d, J=8.6Hz, 2H), 7.70 (d, J=8.6 Hz, 2H), 7.36 (s, 1H), 4.10 (s, 3H), 2.96 (s,3H), 1.29 (s, 9H).

A105a.3:7-[4-(Aminomethyl)phenyl]-1,5-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-(t-butyloxycarbonylamine)

A105a.2 (0.43 g, 13.9 mmol) was dissolved in ethanol (50 mL, 100%ethanol) pre-saturated with ammonia gas. Raney nickel (˜0.5 g) waswashed with water followed by ethanol and then added to the reactionmixture. A balloon of hydrogen gas was affixed to the reaction mixtureand stirred at room temperature for 18 h. The reaction mixture wasfiltered through celite and the solvent removed under reduced pressureto yield A105a (0.4 g, 98%) HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.24 min, M+H⁺=407.28.

Examples A105-A130 was prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of the carboxylic acid in dimethylformamide (DMF)(0.038 mmol;1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol in DMF(0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq). The reactor was agitated for 10 minutes via orbital shaker.Then 150 uL of a solution of 0.2 molar amine in DMF (0.03 mmol; 1 eq)and diisopropylethylamine (0.150; 5 eq) was added to each reactor welland the reactor was agitated for 16 hours at 65° C. The library wasdried via centrifugal evaporation and BOC groups were removed by adding600 uL of a 30% by volume solution of trifluoroacetic acid (TFA) indichloromethane (DCM) and the reactor was agitated for 2 hours. Thelibrary was dried via centrifugal evaporation and was dissolved in 600uL of DMF and 600 uL of methanol (MeOH). The entire contents for eachreactor were transferred to an STR plate was was purified by standardpreparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient 35-90% MeOH over 15min, 20×100 mm 5 μm YMC ODS-A column) utilizing mass-directedfractionation. The purified sample was reconstituted in 1:1/MeOH:DCE,transferred to a tared 2.5 mL plastic microtube, dried via centrifugalevaporation and weighed. The final product was analyzed by HPLC-MS(H₂O/MeOH/0.1% TFA). Examples prepared by this method are described inTable A3. TABLE A3

HPLC Retention MS Ex. R Name (min) Reported A105 CH₃—N-[[4-[1,6-dihydro-1-methyl- 2.06 349.48 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-acetamide A106 CH₃CH₂—N-[[4-[1,6-dihydro-1-methyl- 2.18 363.52 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- propanamide A107

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-methyl propanamide 2.31377.52 A108

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2,2- dimethyl-propanamide2.49 391.54 A109

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- cyclopropanecarboxamide2.27 375.48 A110

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1-methyl-cyclopropanecarboxamide 2.40 389.54 A111

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1-hydroxy-cyclopropanecarboxamide 2.12 391.48 A112

1-cyano-N-[[4-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- cyclopropanecarboxamide2.32 400.48 A113

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-hydroxy- acetamide 1.95365.51 A114

2-cyano-N-[[4-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-acetamide 2.07 374.47 A115

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3- methoxy-propanamide 2.15393.48 A116

4-(aminosulfonyl)-N-[[4-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-butanamide 1.99 456.37 A117

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-benzamide 2.61 411.44 A118

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzeneacetamide 2.63425.44 A119

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3- thiophenecarboxamide2.52 417.39 A120

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1,2,3-thiadiazole-4-carboxamide 2.35 419.37 A121

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4-methyl-1,2,3-thiadiazole-5- carboxamide 2.49 433.41 A122

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1H- tetrazole-5-acetamide2.04 417.44 A123

2-amino-N-[[4-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-acetamide 1.77 364.49 A124

N-[[4-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2- (methylamino)-acetamide1.78 378.48 A125

3-amino-N-[[4-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- propanamide 1.81 378.48A126

(2S)-N-[[4-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2- (methylamino)propanamide1.86 392.50 A127

(2S)-2-amino-N-[[4-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4- methylpentanamide 2.20420.49 A128

(alphaS)-alpha-amino-N-[[4- [1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]benzeneace tamide 2.13 440.41 A129

(2S)-N-[[4-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2- pyrrolidinecarboxamide1.86 404.49 A130

(2S,4R)-N-[[4-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4-hydroxy-2-pyrrolidinecarboxamide 1.81 420.48

Example A1317-[3-(1-aminoethyl)phenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A solution of A56.1d (663 mg, 1.43 mmol) and concentrated HCl solution(4.0 ml) in n-butanol (6.0 ml) was heated to 150° C. for 25 minutesunder micromave which was concentrated to yield A131 (525 mg, 93%).HPLC: 91%, retention time: 1.88 minute (condition B). LC/MS(M+H)⁺=321.3, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.20 (1H, s), 7.87 (1H, s),7.76 (1H, d, J=7.63 Hz), 7.50 (1H, t, J=7.63 Hz), 7.36 (1H, d, J=7.12Hz), 7.20 (1H, s), 4.49 (1H, d, J=6.61 Hz), 4.08-4.14 (3H, m), 3.21 (3H,s), 1.65 (3H, d, J=7.12 Hz).

Example A1327-[3-(1-tert-butyloxycarbonylaminoethyl)phenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A solution of A131 (515 mg, 1.31 mmol) and Et₃N (0.749 ml, 5.18 mmol) indichloromethane (6.5 ml) and DMF (6.5 ml) at 0-5° C. was added (BOC)₂O(300 mg, 1.38 mmol) which was warmed up to RT and stirred for 30minutes. The reaction mixture was concentrated and diluted with CH₂Cl₂(100 ml). The organic phase was washed with saturated NaHCO₃ solution(20 ml), water (20 ml), brine (20 ml) and the organic layer was driedover sodium sulfate. Filtration and concentration to yield a crudeproduct which was added Et₂O (20 ml) and stirred for 10 minutes. Thesolid was collected as A132 (432 mg, 79%). HPLC: 97%, retention time:2.621 minute (condition A). LC/MS (M+H)⁺=421.4. ¹H-NMR (400 MHz, CD₃OD)δ ppm 7.79 (1H, s), 7.62 (1H, s), 7.54 (1H, d, J=7.63 Hz), 7.27 (1H, t,J=7.63 Hz), 7.10 (1H, d, J=8.14 Hz), 6.94 (1H, s), 4.66 (1H, s), 4.03(3H, s), 3.05 (3H, s), 1.30-1.44 (12H, m).

Examples A133 and A134

A133.1:7-[3-(1-tert-butyloxycarbonylaminoethyl)phenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-tert-butyloxycarbonylamine

A solution of A131 (721 mg, 1.71 mmol) and DMAP ((21 mg, 0.17 mmol) inCH₃CN (13 mL) and DMF (13 mL) at RT was added (BOC)₂O (1.30 g, 5.99mmol) which was heated to 50° C. for 16 hrs. The reaction mixture wasconcentrated and diluted with CH₂Cl₂ (100 mL). The organic phase waswashed with water (20 ml×2), brine (20 ml) and the organic layer wasdried over Sodium sulfate. Filtration and concentration to yield aproduct A133.1 (965 mg, 100%). HPLC: 84%, retention time: 3.060 minute(condition A). LC/MS (M+H)⁺=521.3.

A133.2 Chiral Separation of A133.1

Compound A133.1 (965 mg, 1.85 mmol) was subjected to chiral separationto yield A133.2 (312 mg, 65%). HPLC: 97%, retention time: 3.098 minute(LC/MS (M+H)⁺=521.35. and Compound A133.3 (336 mg, 70%). HPLC: >98%,retention time: 3.113 minute LC/MS (M+H)⁺=521.34.

Example A133

A solution of A133.2 (336 mg, 0.65 mmol) in CH₂Cl₂ (2 ml) was added TFA(0.5 ml) dropwise at 0-5° C. which was warmed up to RT and stirred for 1hr. The reaction mixture was concentrated and added Et₂O (20 ml),stirred for 10 minutes. The solid was collected as A133 (335.6 mg, 95%).HPLC: >98%, retention time: 1.860 minute (condition B). Chiral HPLC:100% ee. retention time: 7.57 minute (condition F). LC/MS (M+H)⁺=321.3,¹H-NMR (400 MHz, CD₃OD) δ ppm 8.02 (1H, s), 7.70-7.82 (1H, m), 7.45 (1H,t, J=7.63 Hz), 7.28 (1H, d, J=7.63 Hz), 7.11 (1H, s), 4.44 (1H, d,J=7.12 Hz), 4.05 (3H, s), 3.15 (3H, s), 1.61 (3H, d, J=7.12 Hz).

Example A134

A solution of A133.3 (312 mg, 0.6 mmol) in CH₂Cl₂ (2 ml) was added TFA(0.5 ml) dropwise at 0-5° C. which was warmed up to RT and stirred for 1hr. The reaction mixture was concentrated and added Et₂O (20 ml),stirred for 10 minutes. The solid was collected as A134 (312.5 mg, 95%).HPLC: >98%, retention time: 1.870 minute (condition B). Chiral HPLC:100% ee. retention time: 9.47 minute (condition F). LC/MS (M+H)⁺=321.3,¹H-NMR (400 MHz, CD₃OD) δ ppm 8.02 (1H, s), 7.70-7.80 (1H, m), 7.44 (1H,t, J=7.63 Hz), 7.29 (1H, s), 7.10 (1H, s), 4.44 (1H, d, J=6.61 Hz), 4.05(3H, s), 3.14 (3H, s), 1.61 (3H, d, J=6.61 Hz).

Examples A135-A152

Examples A135-A152 was prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of the carboxylic acid in dimethylformamide (DMF)(0.038 mmol;1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol in DMF(0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq). The reactor was agitated for 10 minutes via orbital shaker.Then 150 uL of a solution of 0.2 molar amine in DMF (0.03 mmol; 1 eq)and diisopropylethylamine (0.150; 5 eq) was added to each reactor welland the reactor was agitated for 16 hours at 65° C. The library wasdried via centrifugal evaporation and for those compounds whichcontained a BOC group, were removed by adding 600 uL of a 30% by volumesolution of trifluoroacetic acid (TFA) in dichloromethane (DCM) and thereactor was agitated for 2 hours. The library was dried via centrifugalevaporation and was dissolved in 600 uL of DMF and 600 uL of methanol(MeOH). The entire contents for each reactor were transferred to an STRplate was was purified by standard preparative HPLC-MS (H₂O/MeOH/0.1%TFA, gradient 35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column)utilizing mass-directed fractionation. The purified sample wasreconstituted in 1:1/MeOH:DCE, transferred to a tared 2.5 mL plasticmicrotube, dried via centrifugal evaporation and weighed. The finalproduct was analyzed by HPLC-MS (H₂O/MeOH/0.1% TFA). Compounds wereisolated as trifluoroacetate salts. Examples prepared by this method aredescribed in Table A4. TABLE A4 Enantiomer A

HPLC Retention MS Ex. R Name (min) Reported A135 CH₃CH₂—N-[1-[3-[1,6-dihydro-1- 2.40 377.61 methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-propanamide A136

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2-hydroxy- acetamide 2.20379.59 A137

2-cyano-N-[1-[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-acetamide 2.27 388.57 A138

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]- cyclopropanecarboxamide2.47 389.60 A139

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2-methyl- propanamide 2.51391.64 A140

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-1-methyl-cyclopropanecarboxamide 2.63 403.60 A141

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-1-hydroxy-cyclopropanecarboxamide 2.34 405.55 A142

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3-methyl- butanamide 2.72405.61 A143

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2,2- dimethyl-propanamide2.71 405.61 A144

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2-ethoxy- acetamide 2.55407.61 A145

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3-methoxy- propanamide 2.35407.60 A146

1-cyano-N-[1-[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]- cyclopropanecarboxamide2.51 414.57 A147

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3,3- dimethyl-butanamide2.90 419.61 A148

2-(acetylamino)-N-[1-[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]ethyl]-acetamide 2.18 420.58 A149

2-(acetyloxy)-N-[1-[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]ethyl]-acetamide 2.32 421.53 A150

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3-hydroxy-3-methyl-butanamide 2.42 421.61 A151

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3-ethoxy- propanamide 2.49421.58 A152

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2-methoxy- acetamide 2.36393.58

Examples A153-A167

Examples A153-A167 were prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of the carboxylic acid in dimethylformamide (DMF)(0.038 mmol;1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol in DMF(0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq). The reactor was agitated for 10 minutes via orbital shaker.Then 150 uL of a solution of 0.2 molar amine in DMF (0.03 mmol; 1 eq)and diisopropylethylamine (0.150; 5 eq) was added to each reactor welland the reactor was agitated for 16 hours at 65° C. The library wasdried via centrifugal evaporation and for those compounds whichcontained a BOC group, were removed by adding 600 uL of a 30% by volumesolution of trifluoroacetic acid (TFA) in dichloromethane (DCM) and thereactor was agitated for 2 hours. The library was dried via centrifugalevaporation and was dissolved in 600 uL of DMF and 600 uL of methanol(MeOH). The entire contents for each reactor were transferred to an STRplate was was purified by standard preparative HPLC-MS (H₂O/MeOH/0.1%TFA, gradient 35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column)utilizing mass-directed fractionation. The purified sample wasreconstituted in 1:1/MeOH:DCE, transferred to a tared 2.5 mL plasticmicrotube, dried via centrifugal evaporation and weighed. The finalproduct was analyzed by HPLC-MS (H₂O/MeOH/0.1% TFA). Compounds wereisolated as trifluoroacetate salts. Examples prepared by this method aredescribed in Table A5. TABLE A5 Enantiomer B

HPLC Retention MS Ex. R Name (min) Reported A153 CH₃CH₂—N-[1-[3-[1,6-dihydro-1- 2.37 377.59 methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-propanamide A154

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2-methyl- propanamide 2.51391.61 A155

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2,2- dimethyl-propanamide2.69 405.61 A156

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]- cyclopropanecarboxamide2.45 389.60 A157

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-1-methyl-cyclopropanecarboxamide 2.61 403.59 A158

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-1-hydroxy-cyclopropanecarboxamide 2.31 404.80 A159

1-cyano-N-[1-[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]- cyclopropanecarboxamide2.49 414.57 A160

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2-hydroxy- acetamide 2.17378.72 A161

2-cyano-N-[1-[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-acetamide 2.25 388.57 A162

2-(acetylamino)-N-[1-[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]ethyl]-acetamide 2.14 420.57 A163

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-2- (dimethylamino)-acetamide2.00 406.61 A164

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3-methyl- butanamide 2.70405.61 A165

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-4-methyl- pentanamide 2.90419.61 A166

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3,3- dimethyl-butanamide2.89 419.55 A167

N-[1-[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]ethyl]-3-methoxy- propanamide 2.32407.57

Example A1681,6-dihydro-1-methyl-4-(methylamino)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylicacid

A168.1:4-[[(1,1-dimethylethoxy)carbonyl]methylamino]-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylicacid

A1.12 (0.3 g, 0.74 mmol), pyruvic acid (98 mg, 1.12 mmol), triethylamineand palladium dibenzylidene acetone (68 mg, 0.074 mmol) in dry DMF (3mL) were heated to 120 C for 15 min in a microwave. The reaction mixturewas diluted with water (3 mL) and extracted with ethyl acetate (10 mL).The organic extract was discarded and the aqueous layer acidified to pH3-4 using 1N HCl. The acidified aqueous layer was then extracted withethyl acetate (3×20 mL), the combined organics dried (MgSO₄) andevaporated in vacuo to give A168.1 (161 mg, 62%). HPLC YMC S-5 4.6×33 mm(2 min grad): retention time 1.32 min, M+H⁺=346.31, NMR (400 MHz, DMSO)δ 12.49 (s, 1H), 8.16 (s, 1H), 7.47 (s, 1H), 4.04 (s, 3H), 3.29 (s, 3H),1.30 (s, 9H).

A168.2:1,6-dihydro-1-methyl-4-(methylamino)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxylicacid

A168.1 (20 mg, 0.058 mmol) was dissolved in 4N HCl in dioxane (3 mL) andthe resulting suspension stirred at room temperature for 3 hrs. Thereaction mixture was evaporated in vacuo, triturated with diethyl ether,then filtered to give A168 (11.2 mg, 88%). HPLC YMC S-5 4.6×33 mm (2 mingrad): retention time 0.83 min, M+H⁺=246.15. NMR (400 MHz, DMSO) δ 8.65(s, 1H), 7.42 (s, 1H), 4.10 (s, 3H), 3.10 (s, 3H).

Examples A169-A172

Examples A169-A172 were prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of the carboxylic acid in dimethylformamide (DMF)(0.038 mmol;1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol in DMF(0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq). The reactor was agitated for 10 minutes via orbital shaker.Then 150 uL of a solution of 0.2 molar amine in DMF (0.03 mmol; 1 eq)and diisopropylethylamine (0.150; 5 eq) was added to each reactor welland the reactor was agitated for 16 hours at 65° C. The library wasdried via centrifugal evaporation and the BOC group was removed byadding 600 uL of a 30% by volume solution of trifluoroacetic acid (TFA)in dichloromethane (DCM) and the reactor was agitated for 2 hours. Thelibrary was dried via centrifugal evaporation and was dissolved in 600uL of DMF and 600 uL of methanol (MeOH). The entire contents for eachreactor were transferred to an STR plate was was purified by standardpreparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient 35-90% MeOH over 15min, 20×100 mm 5 μm YMC ODS-A column) utilizing mass-directedfractionation. The purified sample was reconstituted in 1:1/MeOH:DCE,transferred to a tared 2.5 mL plastic microtube, dried via centrifugalevaporation and weighed. The final product was analyzed by HPLC-MS(H₂O/MeOH/0.1% TFA). Compounds were isolated as trifluoroacetate salts.Examples prepared by this method are described in Table A6. TABLE A6

HPLC Retention MS Ex. R Name (min) Reported A169

1,6-dihydro-1-methyl-4- (methyl amino)-N-(1- methylethyl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7- carboxamide 1.76 287.51 A170

1,6-dihydro-1-methyl-4- (methylamino)-N-(2,2,2-trifluoroethyl)-imidazo[4,5- d]pyrrolo[2,3-b]pyridine-7- carboxamide1.81 327.52 A171

N-ethyl-1,6-dihydro-1- methyl-4-(methylamino)-imidazo[4,5-d]pyrrolo[2,3- b]pyridine-7-carboxamide 1.51 273.46 A172

1,6-dihydro-1-methyl-4- (phenylmethyl)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7- carboxamide 2.20 335.51

Examples A173-A213

Examples A173-A213 was prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of either a carboxylic acid in dimethylformamide (DMF) (0.038mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol inDMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq) or an isocyanate or sulfonylchloride reagent with pyridine insimilar molar ratio to the carboxylic acid reagent. The reactor wasagitated for 10 minutes via orbital shaker. Then 150 uL of a solution of0.2 molar amine in DMF (0.03 mmol; 1 eq) and diisopropylethylamine(0.150; 5 eq) was added to each reactor well and the reactor wasagitated for 16 hours at 65° C. The library was dried via centrifugalevaporation and BOC groups were removed by adding 600 uL of a 30% byvolume solution of trifluoroacetic acid (TFA) in dichloromethane (DCM)to each reactor (that had a BOC group) and the reactor was agitated for2 hours. The library was dried via centrifugal evaporation and wasdissolved in 600 uL of DMF and 600 uL of methanol (MeOH). The entirecontents for each reactor were transferred to an STR plate was waspurified by standard preparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column) utilizingmass-directed fractionation. The purified sample was reconstituted in1:1/MeOH:DCE, transferred to a tared 2.5 mL plastic microtube, dried viacentrifugal evaporation and weighed. The final product was analyzed byHPLC-MS (H₂O/MeOH/0.1% TFA). Compounds were isolated as trifluoroacetatesalts. Examples prepared by this method are described in Table A7. TABLEA7

HPLC Retention MS Ex. Z Name (min) Reported A173

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N′-(1,1-dimethylethyl)-urea 2.68 406.62 A174

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N′-(4- methoxyphenyl)-urea2.72 456.56 A175

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1- propanesulfonamide 2.54413.55 A176

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- ethanesulfonamide 2.29399.55 A177

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzeneethanesulfonamide2.96 475.49 A178

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4-methoxy-benzenesulfonamide 2.79 477.48 A179

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3- methoxy-benzeneacetamide2.67 455.55 A180

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N′- (phenylmethyl)-urea2.69 440.57 A181

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzenemethanesulfonamide2.80 461.55 A182

4-chloro-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzenesulfonamide 3.00481.46 A183

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4- methoxy-benzamide 2.76441.55 A184

N-(4-chlorophenyl)-N′-[[3- [1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-urea 3.10 460.49 A185

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-yl]phenyl]methyl]-N′-(2- phenylethyl)-urea 2.87 454.61 A186

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- butanamide 2.47 377.64A187

[[3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-yl]phenyl]methyl]-carbamic acid, phenyl ester 2.83 427.55 A188

[[3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-carbamic acid, phenylmethylester 2.95 441.55 A189

[[3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-carbamic acid, ethyl ester2.54 379.60 A190

[[3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-carbamic acid,2-methylpropyl ester 2.94 407.60 A191

[[3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-carbamic acid,4-methoxyphenyl ester 2.95 457.55 A192

[[3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-carbamic acid, methyl ester2.36 365.60 A193

[[3-[1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-carbamic acid,4-chlorophenyl ester 3.12 461.49 A194

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N′-phenyl- urea 2.77 426.57A195

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- benzenesulfonamide 2.75447.53 A196

(2R)-2-amino-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3-hydroxy-3-methylbutanamide 1.96 422.59 A197

(2S)-2-amino-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3-hydroxy-3-methylbutanamide 1.96 422.62 A198

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3- (dimethylamino)-propanamide 1.86 406.61 A199

N-[2-[[[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]amino]-2-oxoethyl]-benzamide 2.40 468.54 A200

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3- pyridinecarboxamide 2.09412.56 A201

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2- pyrazinecarboxamide 2.37413.55 A202

2-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-acetamide 2.10 374.57 A203

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2- methoxy-acetamide 2.18379.62 A204

(alphaS)-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-alpha-(dimethylamino)benzeneprop- anamide 2.34 482.56 A205

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-4-(dimethylamino)-butanamide 1.90 420.62 A206

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1- piperidinepropanamide1.98 445.84 A207

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]- cyclohexaneacetamide 3.00431.61 A208

(alphaS)-N-[[3-[1,6-dihydro- 1-methyl-4- (methylammo)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-alpha- methoxy-alpha-(trifluoromethyl)benzeneaceta- mide 3.04 523.50 A209

(alphaR)-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-alpha- methoxy-alpha-(trifluoromethyl)benzeneaceta- mide 3.03 523.52 A210

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-alpha-hydroxy-alpha-methyl- benzeneacetamide 2.57 455.56 A211

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2,5-dioxo-4-imidazolidineacetamide 1.96 447.54 A212

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3,3,3-trifluoro-2-hydroxy-2-methyl- propanamide 2.42 447.50 A213

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-hydroxy-2-methyl-propanamide 2.17 393.61

Example A214N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-acetamide

A214.1: 2-((6-Bromopyridin-2-yl)methyl)isoindoline-1,3-dione

A mixture of commercially available (6-bromopyridin-2-yl)methanol (20.0g, 0.106 mol), phthalimide (20.4 g, 0.138 mol), and triphenylphosphine(36.2 g, 0.138 mol), and 1,1′-(azodicarbonyl)-dipiperidine (34.8 g,0.138 mol) in anhydrous tetrahydrofuran (1 L) was stirred at roomtemperature overnight. The precipitate was collected by vacuumfiltration and washed with tetrahydrofuran. The filtrate wasconcentrated under reduced pressure, and the solid residue wastriturated with methanol with sonication. A214.1 was collected by vacuumfiltration and was dried well to give 24.1 g as a white solid. Thefiltrate still contained significant product which could be isolated asa second crop with methanol trituration. The compound had an HPLCretention time=2.32 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.;Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O,and 0.1% TFA) and a LC/MS M⁺¹=317.15 and 319.15.

Alternate Preparation of A214.1

A214.1a: 2-Chloromethyl-6-bromopyridine

A 1000 mL round bottom flask was flame dried, then cooled under a streamof dry nitrogen. To the flask was added commercially available6-bromopyridin-2-yl)methanol (25 g, 133 mmol) along with dichloromethane(300 mL). While stirring at room temperature under a nitrogenatmosphere, thionyl chloride (14.5 mL, 199.4 mmol) was added dropwiseover 7 to 8 minutes. A white precipitate immediately formed, thenredissolved after 10-15 minutes to give a clear, pale yellow solution.After 20-25 minutes post addition, a precipitate re-formed. The reactionwas stirred for 3 hours at room temperature then an additional aliquotof thionyl chloride (3.5 mL) was added and the reaction was stirred for45 minutes. The solution was evaporated to dryness to give thehydrochloride salt of A214.1a as a pale yellow solid (95% purity by HPLCanalysis). The material was used for subsequent reactions withoutfurther purification. The compound had an HPLC retention time=2.21 min.(Column: Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90%H₂O, and 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, and 0.2% H₃PO₄) and aLC/MS M⁺¹=208.2 (100% peak).

Alternate Preparation A214.1a

6-bromopyridin-2-yl)methanol (1 kg) was dissolved in dichloromethane (10L). Thionyl chloride (3 kg) was added dropwise and the reaction mixturestirred at room temperature for 6 h. TLC analysis indicateddisappearance of the starting material. The solvent was removed underreduced pressure and diluted with additional dichloromethane (2 L) andthe solvent was removed under reduced pressure. The crude productA214.1a (1.25 kg) contained some residual solvent. The material was usedin the next step without further purification.

A214.1: 2-((6-Bromopyridin-2-yl)methyl)isoindoline-1,3-dione

Alternate Preparation:

A214.1a (133 mmol) was dissolved in DMF (250 mL) and potassiumphthalimide (54.2 g, 293 mmol) was added portionwise to maintain theinternal temperature below 30° C. An additional portion of DMF (50 mL)was used to rinse the flask and powder funnel used for the potassiumphthalimide addition. The reaction was stirred at room temperatureovernight after which the reaction was judged complete by HPLC analysis.Water (600 mL) was added slowly to the reaction and after 30 minutes ofstirring the resulting precipitate was collected by filtration, washedwith several portions of water (1000 mL total) and allowed to air dry.The resulting solid, which contained the desired product along withexcess phthalimide, was resuspended in water (700 mL) and the solutionwas made basic by addition of 1 N NaOH (3 mL). After slurrying for 20minutes the solids were collected by filtration, washed with severalportions of water and allowed to air dry. The solid still contained somephthalimide so was resuspended in MeOH (50 mL) and water (800 mL) andallowed to stir vigorously for 2 days. The solid was again collected byfiltration, then slurried in hot MeOH (200-300 mL), cooled to roomtemperature and filtered. The solid was air dried to afford thephthalimide adduct, A214.1, along with residual phthalimide as a whitesolid. This material was used without further purification for the nextstep.

Alternate Preparation

Potassium pthalimide (1.23 kg, 6.0 mol), potassium carbonate (2.07 kg,15 mol) were dissolved in DMF (12.5 L). A214.1a was added slowly and thereaction stirred at room temperature overnight. TLC analysis indicateddisappearance of starting material. The product was filtered to yieldA214.1 (2.5 kg wet weight—used in next step without further drying).

A214.2: (6-Bromopyridin-2-yl)methanamine

A suspension of A214.1 in absolute ethanol (420 mL) was heated at 70° C.for 30 min. To the heterogeneous solution was added hydrazinemonohydrate. Within a minute, the reaction mixture became homogeneous.The reaction mixture was heated for 3 hr., during which time the mixturesolidified into a white solid. An additional 100 mL of ethanol wasadded, and the mixture was filtered. The precipitate was washed wellwith ethanol, and the filtrate was partially concentrated. The solid wascollected by vacuum filtration. The filtrated was concentrated todryness and triturated with methanol. A214.2 was collected by vacuumfiltration to give 14.3 g (93%) as a white solid. The compound had anHPLC retention time=0.395 min. (Column: Chromolith SpeedROD 4.6×50 mm—4min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10%H₂O, and 0.1% TFA) and a LC/MS M⁺¹=187.12 and 189.12.

Alternate Preparation A214.2

A214.1 (1.8 kg, 5.7 mol) was suspended in methanol (18 L) at 65° C.Hydrazine hydrate (1.5 kg, 28 mol) was added over 30 minutes in 500 gbatches. After 15 minutes the reaction became homogenious and was heatedfor 4 hours at 65° C. TLC analysis showed the disappearance of startingmaterial. The reaction mixture was allowed to cool. The product wasfiltered and washed with additionl methanol, stirred with methyl t-butylether, filtered and dried to yield A214.2 (800 g, 75%).

A214.3: N-((6-Bromopyridin-2-yl)methyl)acetamide

To a mixture of A214.2 (14.3 g, 76.5 mmol) and pyridine (14.3 mL) inanhydrous tetrahydrofuran (250 mL) was added acetic anhydride (14.3 mL),and the reaction mixture was stirred for 3 hr at room temperature. Thesolvent was removed under reduced pressure, and the oily residue wasdiluted with dichloromethane, washed with water, washed with a saturatedaqueous solution of sodium bicarbonate, and dried over anhydrous sodiumsulfate. Concentration followed by drying under reduced pressureafforded 16.3 g (93%) of A214.3 as an off-white solid. The compound hadan HPLC retention time=0.987 min. (Column: Chromolith SpeedROD 4.6×50mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90%MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=229.10 and 231.10.

A214.4: N-((6-((Trimethylsilyl)ethynyl)pyridin-2-yl)methyl)acetamide

To a mixture of A214.3 (8.0 g, 34.9 mmol),dichlorobis(triphenylphosphine)palladium II (1.47 g, 2.09 mmol), andcopper iodide (0.332 g, 1.75 mmol) in anhydrous dimethylformamide (90mL) degassed well with nitrogen was added trimethylsilylacetylene (7.4mL, 52.4 mmol) followed by triethylamine (24.3 mL, 0.175 mol). Thereaction mixture was immersed in an oil bath at 75° C. and stirred for 2hr. The solvent was removed under reduced pressure, and the residue waspurified by flash silica gel chromatography using a mixture of methanolin dichloromethane (2%-5%) to give 7.42 g (86%) of A214.4 as a reddish,viscous oil. The compound had an HPLC retention time=2.42 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=247.20.

A214.5: N-((6-Ethynylpyridin-2-yl)methyl)acetamide

A mixture of A214.4 (4.96 g, 20.1 mmol) and catalytic potassiumcarbonate (0.295 g, 2.13 mmol) in anhydrous methanol (50 mL) was stirredat room temperature for 10 min. The residual potassium carbonate wasremoved by vacuum filtration, and the filtrate was concentrated underreduced pressure. The residue was purified by flash silica gelchromatography using a mixture of methanol in dichloromethane (2%-5%) toafford 2.64 g (75%) of A214.5 as a tan solid. The compound had an HPLCretention time=0.602 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.;Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O,and 0.1% TFA) and a LC/MS M⁺¹=175.20.

A214.6 tert-Butyl7-((6-(acetamidomethyl)pyridin-2-yl)ethynyl)-6-amino-1-methyl-1H-imidazo-[4,5-c]pyridin-4-yl(methyl)carbamate

To a mixture of A214.5 (1.00 g, 5.74 mmol),tert-Butyl6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate(1.78 g, 4.42 mmol), dichlorobis(triphenyl-phosphine)palladium II (0.186g, 0.265 mmol), and copper iodide (0.042 g, 0.221 mmol) in anhydrousdimethylformamide (12 mL) degassed well with nitrogen was addeddiisopropylamine (15 mL, 0.111 mol). The reaction mixture was immersedin an oil bath at 75° C. and stirred for 45 min. The solvent was removedunder reduced pressure, and the residue was purified by flash silica gelchromatography using a mixture of methanol in dichloromethane (5%-8%) togive 1.88 g (95%) of A214.6 as a tan solid. The compound had an HPLCretention time=2.13 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.;Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O,and 0.1% TFA) and a LC/MS M⁺¹=450.35.

A214.7: tert-Butyl7-(6-(acetamidomethyl)pyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

To a solution of A214.6 (1.95 g, 4.34 mmol) in 25 mL of anhydrousdimethylacetamide under nitrogen was added a 1.0 M solution of potassiumtert-butoxide in tetrahydrofuran (4.8 mL, 4.77 mmol), and the reactionmixture was heated for 10 min. A second 4.8 mL was added, and thereaction was still incomplete after an addition 10 min. A thirdequivalent was added, and the reaction mixture was stirred for 10 min.by HPLC and TLC, the reaction was complete. The solvent was removedunder reduced pressure, and the residue was purified by flash silica gelchromatography using a 5% mixture of methanol in dichloromethane to give0.780 g of A214.7 as a yellow solid and 0.284 g of 1 as a yellow solid.The combined products represented >55% yield. The compound (1G) had anHPLC retention time=2.20 min. (Column: Chromolith SpeedROD 4.6×50 mm—4min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10%H₂O, and 0.1% TFA) and a LC/MS M⁺¹=450.37.

A214.8:N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-acetamide

A solution of A214.7 (0.394 g, 0.876 mmol) in trifluoroacetic acid (14mL) was stirred at room temperature for 10 min. The trifluoroacetic acidwas removed under reduced pressure, and the residue was diluted withdichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate, and dried over anhydrous sodium sulfate. After filtration,the sodium sulfate remained a bright yellow and was subsequently washedwith ethyl acetate followed by a 5% mixture of methanol indichloromethane, which removed the color. The combined organic layerswere concentrated and purified by flash silica gel chromatography usinga 5% methanol in dichloromethane to give 275 g (90%) of A214 as a yellowsolid. The compound had an HPLC retention time=1.73 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=350.35. ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.98 (s, 3H) 2.98 (d, J=4.83Hz, 3H) 4.02 (s, 3H) 4.40 (d, J=5.27 Hz, 2H) 6.69 (d, J=4.83 Hz, 1H)7.02 (d, J=7.47 Hz, 1H) 7.32 (d, J=1.76 Hz, 1H) 7.67-7.75 (m, 2H) 7.90(s, 1H) 8.56 (t, J=5.27 Hz, 1H) 11.77 (s, 1H)

Example A2157-[6-(aminomethyl)-2-pyridinyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A mixture of A214 (0.168 g, 0.481 mmol), n-butanol (3 mL), andconcentrated hydrochloric acid (2 mL) was heated in the microwave at150° C. for 30 min. The reaction mixture was concentrated to drynessunder reduced pressure, and the residue was diluted withdichloromethane, washed with a mixture of saturated aqueous solution ofsodium bicarbonate and 1N aqueous sodium hydroxide, and dried overanhydrous sodium sulfate. Concentration under reduced pressure afforded0.028 g of A215 as a yellow solid. Additional product was still in theaqueous layer. Further extractions with ethyl acetate anddichloromethane afforded an additional 88 mg of A215. The compound hadan HPLC retention time=1.66 min. (Column: Chromolith SpeedROD 4.6×50mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90%MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M+¹=308.33. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.68 (brs, 2H) 3.18 (d, J=5.27 Hz, 3H) 3.94 (d, J=4.39 Hz,2H) 3.97-4.02 (m, 1H) 4.04 (s, 3H) 5.54 (d, J=5.27 Hz, 1H) 6.98-7.03 (m,2H) 7.49-7.53 (m, 1H) 7.55-7.63 (m, 2H) 9.86 (s, 1H)

A215.1:7-(6-(Aminomethyl)pyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-aminetrihydrochloride

A mixture of A214 (1.60 g, 3.55 mmol), absolute ethanol (30 mL), andconcentrated hydrochloric acid (30 mL) was heated at 80° C. for 7 hr.The reaction mixture was concentrated to dryness and dried well underreduced pressure to give 1.48 g (100%) of A215-trihydrochloride salt asa yellow solid. The compound had an HPLC retention time=1.23 min.(Column: Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90%H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and aLC/MS M⁺¹=308.35.

Example A216N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-3-methoxy-propanamide

To a mixture of A215 (0.020 g, 0.065 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.019 g,0.098 mmol), 1-hydroxybenzotriazole (0.013 g, 0.098 mmol), anddiisopropylethylamine (0.034 mL, 0.195 mmol) in anhydrousdimethylformamide (2 mL) was added 3-methoxypropionic acid (9.20 μL,0.098 mmol). The reaction mixture was stirred at room temperatureovernight (After ˜3 hr, the reaction mixture became homogenous). Thesolvent was removed under reduced pressure, and the residue was dilutedwith dichloromethane, washed with water, and dried over anhydrous sodiumsulfate. Concentration under pressure followed by purification by flashsilica gel chromatography using a 5% mixture of methanol indichloromethane afforded 0.018 g (69%) of A216 as a yellow solid. Thecompound had an HPLC retention time=1.84 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA;Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=394.37. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.62 (t, J=7.15 Hz, 2H) 3.15 (d, J=6.60 Hz,3H) 3.54 (s, 3H) 3.78 (t, J=7.15 Hz, 2H) 4.01 (s, 3H) 4.56 (d, J=6.10Hz, 2H) 5.49-5.54 (m, 1H) 6.96-6.98 (m, 2H) 7.51-7.58 (m, 3H) 9.98 (s,1H)

Example A217N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2,2-dimethyl-propanamide

To a mixture of A215 (0.020 g, 0.065 mmol) and triethylamine (0.045 mL,0.326 mmol) in dichloromethane (2 mL) was added trimethylacetyl chloride(9.00 μL, 0.072 mmol). The reaction mixture was stirred at roomtemperature for 30 min. The reaction mixture was diluted withdichloromethane, washed with water, and dried over anhydrous sodiumsulfate. Concentration under pressure followed afforded 0.020 g (80%) ofA217 as a yellow solid. The compound had an HPLC retention time=2.11min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH,90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and aLC/MS M⁺¹=392.42.

Example A218N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-cyclopropanecarboxamide

To a mixture of A215 (0.020 g, 0.065 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.019 g,0.098 mmol), 1-hydroxybenzotriazole (0.013 g, 0.098 mmol), anddiisopropylethylamine (0.034 mL, 0.195 mmol) in anhydrousdimethylformamide (2 mL) was added cyclopropylcarboxylic acid (8.00 μL,0.098 mmol). The reaction mixture was stirred at room temperatureovernight. Concentration under pressure followed by purification byflash silica gel chromatography using a 5% mixture of methanol indichloromethane afforded 0.012 g (50%) of A218 as a yellow solid. Thecompound had an HPLC retention time=1.99 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA;Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=376.40.

Examples A219-A245

Examples A219-A245 were prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of either a carboxylic acid in dimethylformamide (DMF) (0.038mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol inDMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq) or an isocyanate or sulfonylchloride reagent with pyridine insimilar molar ratio to the carboxylic acid reagent. The reactor wasagitated for 10 minutes via orbital shaker. Then 150 uL of a solution of0.2 molar amine in DMF (0.03 mmol; 1 eq) and diisopropylethylamine(0.150; 5 eq) was added to each reactor well and the reactor wasagitated for 16 hours at 65° C. The library was dried via centrifugalevaporation and BOC groups were removed by adding 600 uL of a 30% byvolume solution of trifluoroacetic acid (TFA) in dichloromethane (DCM)to each reactor (that had a BOC group) and the reactor was agitated for2 hours. The library was dried via centrifugal evaporation and wasdissolved in 600 uL of DMF and 600 uL of methanol (MeOH). The entirecontents for each reactor were transferred to an STR plate was waspurified by standard preparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column) utilizingmass-directed fractionation. The purified sample was reconstituted in1:1/MeOH:DCE, transferred to a tared 2.5 mL plastic microtube, dried viacentrifugal evaporation and weighed. The final product was analyzed byHPLC-MS (H₂O/MeOH/0.1% TFA). Compounds were isolated as trifluoroacetatesalts. Examples prepared by this method are described in Table A8. TABLEA8

HPLC Retention MS Ex. R Name (min) Reported A219

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-1,2,3-thiadiazole-4-carboxamide 2.22 420.48 A220

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-3- hydroxy-3-methyl-butanamide 2.06 408.58 A221

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-4-methyl-1,2,3-thiadiazole-5- carboxamide 2.37 434.53 A222

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-3- (dimethylamino)-propanamide 1.70 407.59 A223

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]- benzamide 2.44412.55 A224

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2- hydroxy-acetamide1.71 366.56 A225

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-3- methyl-butanamide2.43 392.61 A226

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2- hydroxy-2-methyl-propanamide 1.91 394.56 A227

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-3- hydroxy-butanamide1.85 394.60 A228

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2- methoxy-acetamide1.95 380.60 A229

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-1- methyl-cyclopropanecarboxamide 2.20 390.61 A230

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-pyridinecarboxamide 2.35 413.55 A231

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-pyrazinecarboxamide 2.16 414.55 A232

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-3-pyridinecarboxamide 1.93 413.56 A233

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2- methyl-propanamide2.10 378.29 A234

(2S)-2-amino-N-[[6-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]propanamide 2.37379.32 A235

(2S)-N-[[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-(methylamino)propanamide 4.32 391.12 A236

(2S)-N-[[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-pyrrolidinecarboxamide 2.49 405.40 A237

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-(methylamino)-acetamide 1.59 378.97 A238

(2R)-2-amino-N-[[6-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]propanamide 2.47379.19 A239

(2R)-N-[[6-[1,6-dihydro-1- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-(methylamino)propanamide 1.60 393.26 A240

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-cyclopentaneacetamide 2.74 418.36 A241

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-cyclohexanecarboxamide 2.69 418.38 A242

N-[[6-[1,6-dihydro-1-methyl- d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2- methyl-butanamide 2.35 392.38 A243

N-[[6-[1,6-dihydro-1-methyl- d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2- methyl-pentanamide 2.59 406.35 A244

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-4- methyl-pentanamide2.70 406.38 A245

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]- pentanamide 2.50392.38Alternate Preparations of Example A228

N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2-methoxy-acetamide

To a mixture of A215.1-trihydrochloride (1.15 g, 2.76 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.794 g,4.14 mmol), 1-hydroxybenzotriazole (0.559 g, 4.14 mmol), anddiisopropylethylamine (2.90 mL, 16.6 mmol) in anhydrousdimethylformamide (50 mL) was added methoxyacetic acid (0.320 mL, 4.14mmol). The reaction mixture was stirred at 80° C. for 20 min. During thefirst 5 min, the suspension became homogeneous. The solvent was removedunder reduced pressure, and the residue was diluted withdichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate, and dried over anhydrous sodium sulfate. Concentrationunder pressure followed by purification by flash silica gelchromatography using a mixture of methanol in dichloromethane (2%-5%)afforded 0.890 g (85%) of A228 as yellowish-brown solid. The solid wastriturated with methanol to give 0.660 g of A228 as a yellow solid. Thefiltrate was re-purified on silica gel to give an additional 0.191 g ofA228. The compound had an HPLC retention time=1.81 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=380.33.

Alternate Preparation of Example A228

A228.1: N-((6-Bromopyridin-2-yl)methyl)-2-methoxyacetamide

To a mixture of 6-bromo-2-pyridinemethanamine hydrochloride(commercially available or prepared as A214.2) (5.00 g, 222.4 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.44 g,33.6 mmol), 1-hydroxybenzotriazole (4.54 g, 33.6 mmol), anddiisopropylethylamine (16.0 mL, 89.6 mmol) in anhydrousdimethylformamide (100 mL) was added methoxyacetic acid (2.60 mL, 33.6mmol). The reaction mixture was stirred at room temperature for 3 hr andthen concentrated under reduced pressure. The residue was diluted withdichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduce pressure, and the residue was dissolved in aminimum amount of ethyl acetate Oust enough to fully dissolve), loadedonto a fritted funnel containing a pad of Celite topped with a pad ofsilica gel, and flushed with ethyl acetate to give 19.0 g (98%) ofA228.1 as a white solid. The compound had an HPLC retention time=1.15min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH,90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and aLC/MS M⁺¹=259.12 and 261.12.

As an alternative method for purification, 4N hydrochloric acid indioxane (28 mL) was slowly added to a solution of the crude reactionproduct of A228.1 (˜28 g) in ether (400 mL). Filtration and drying underreduced pressure afforded 23.6 g of A228.1 as the hydrochloride salt.

Alternate Preparation of A228.1

A214.2 (800 g, 4.27 mol, processed as 2×400 g batches),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.22 kg,6.4 mol), 1-hydroxybenzotriazole (866 g, 6.4 mol), anddiisopropylethylamine (830 g, 6.4 mol) in anhydrous dimethylformamide(1.6 L) was added methoxyacetic acid (578 g, 6.4 mol). The reactionmixture was heated at 70° C. for 1 h. TLC analysis of the reactionindicated disappearance of the starting material. The solvent wasremoved under reduced pressure. The residue was dissolved indichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduce pressure, and the residue purified by silica gelcolumn chromatography to yield 650 g of A228.1.

A228.2:2-Methoxy-N-((6-((trimethylsilyl)ethynyl)pyridin-2-yl)methyl)acetamide

To a mixture of the hydrochloride salt of A228.1 (13.0 g, 44.0 mmol)[The HCl salt is not necessary for the reaction],dichlorobis(triphenylphosphine)palladium II (1.85 g, 2.64 mmol), andcopper iodide (0.503 g, 2.64 mmol) in anhydrous dimethylformamide (125mL) degassed by bubbling nitrogen through the solution andtrimethylsilylacetylene (9.30 mL, 66.0 mmol) was added via syringefollowed by diisopropylamine (154 mL, 1.10 mol) via cannula. Thereaction mixture was immersed in an oil bath at 80° C. and stirred for30 min. After cooling to room temperature, the salts were removed byvacuum filtration and washed with dimethylformamide. The solvent wasremoved under reduced pressure, and the residue was dissolved in etherand filtered once again to remove additional salts. The filtrate wasconcentrated and purified by flash silica gel chromatography using a 50%mixture of ethyl acetate in hexane to give 11.43 g (94%) of the desiredproduct A228.2 as a light tan solid. The compound had an HPLC retentiontime=2.55 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; SolventA=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1%TFA) and a LC/MS M⁺¹=277.32.

Alternate Preparation of A228.2

A228.1 (650 g, 2.5 mol) dichlorobis(triphenylphosphine)palladium II (87g, 0.125 mol), and copper iodide (23.8 g, 0.125 mol) in anhydrousdimethylformamide (7 L) degassed by bubbling nitrogen through thesolution for 30 min. Trimethylsilylacetylene (9.30 mL, 66.0 mmol) anddiisopropylamine (8.6 L) were added and the reaction mixture immediatelyplaced in a preheated oil bath at 80° C. The reaction mixture wasstirred for 1 h at 80° C. TLC analysis indicated the disappearance ofstarting material. The solvent was removed under reduced pressure andthe residue purified by column chromatography to provide A228.2 (280 g,40%) as a tan solid.

A228.3: N-((6-Ethynylpyridin-2-yl)methyl)-2-methoxyacetamide

A mixture of A228.2 (25.0 g, 90.4 mmol) and a catalytic amount ofpotassium carbonate (1.38 g, 9.95 mmol) in anhydrous methanol (350 mL)was stirred for 15 min. The reaction mixture was filtered under reducedpressure, and the filtrate was concentrated and further dried on ahigh-vacuum pump for ˜15 min. The residue was dissolved in a smallamount of a 2% mixture of methanol in dichloromethane and was loaded ona 2 L coarse fritted funnel containing a pad of Celite topped with a padof silica gel (˜200 g-2 mL/g) and a pad of sand. The product was flushedthrough with 2% methanol in dichloromethane to give three fractionsanalyzed by HPLC: A.) 500 mL—no product (clear), B.) 1800 mL—product(yellow), and C.) 1000 mL—no product (pale yellow). Fraction B wasconcentrated under reduced pressure to give 17.93 g (97%) of A228.3 as alight orange solid, which was ground with a mortal and pestle to give alight tan solid. The compound had an HPLC retention time=0.820 min.(Column: Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90%H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and aLC/MS M⁺¹=205.24. ¹H NMR (400 MHz, DMSO) δ ppm 3.34 (s, 3H) 3.88 (s, 2H)4.32 (s, 1H) 4.36 (d, J=6.10 Hz, 2H) 7.28 (d, J=7.63 Hz, 1H) 7.43 (d,J=7.63 Hz, 1H) 7.77 (t, J=7.88 Hz, 1H) 8.43 (t, J=5.85 Hz, 1H)

A228.4: tert-Butyl6-amino-7-((6-((2-methoxyacetamido)methyl)pyridin-2-yl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

To a 1 L three-neck, round bottom flask equipped with a 250 mL additionfunnel under nitrogen was added tert-butyl6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate(25 g, 62.0 mmol), A228.3 (16.0 g, 78.1 mmol),dichlorobis-(triphenyl-phospine)-palladium (II) (2.61 g, 3.72), andcopper iodide (0.590 g, 3.10 mmol). To the mixture was added 170 mL ofanhydrous dimethylformamide via syringe. An outlet needle was added, andthe mixture was flushed well with a stream of nitrogen for 15 min whilestirring rapidly. The nitrogen outlet was removed, and the reactionmixture was maintained under positive pressure with nitrogen.Diisopropylamine (200 mL, 1.43 mol) was added to the addition funnel viacannula over 5 min. The diisopropylamine was then added to the reactionmixture in ˜0.5 min. Upon completion, the reaction mixture was quicklyimmersed in an oil bath at 98° C., the oil bath was allowed to cool to˜85° C., and the reaction mixture was stirred for 45 min at 85° C. After˜1-2 min, the reaction mixture became dark in color. HPLC analysisindicated that there was still approximately 5% of the iodo startingmaterial remaining as well as dimerized acetylene, but no acetylene wasobserved. The reaction mixture was removed from the bath and allowed tocool to room temperature under nitrogen.

The reaction mixture was concentrated under reduced pressure until onlya small amount of dimethylformamide remained (total volume=64 mL). Thedark residue was diluted with ˜800 mL of ethyl acetate and was pouredinto a 2 L separatory funnel. The homogeneous solution was washed with˜400 mL of a 10% aqueous solution of lithium chloride. After the washingwas complete, the product started crystallizing from the organic layer.The product was allowed to precipitate for 15 min, and the aqueous layerwas drained. The organic layer was filtered through a 600 mL frittedfunnel (medium porosity), and the precipitate was washed with ˜400 mL ofethyl acetate. During this time, a second crop had formed in the aqueouslayer. The aqueous mixture was diluted with ethyl acetate and filteredas before to give additional product. By HPLC, both were of equalpurity, and both were combined, dried under reduced pressure, anddiluted with dichloromethane (˜800 mL) (sonication and gentle heatingwere required). The solution was washed with ˜300 mL of a saturatedaqueous solution of sodium bicarbonate, and the organic layer wascollected. The aqueous layer was extracted with dichloromethane (2×200mL), and the combined organic layers (˜1200 mL) were dried overanhydrous sodium sulfate. Concentration under reduced pressure afforded21.3 g (72%) of A228.4 as a light-brown solid (HPLC AP=>99%).

The filtrates were washed with a 10% aqueous solution of lithiumchloride and dried over anhydrous sodium sulfate. The aqueous layer wasextracted with ethyl acetate (3×), and the organic layer was collectedand dried over anhydrous sodium sulfate. The fritted funnels from theprevious filtrations were rinsed with a 50% mixture of methanol indichloromethane. All three organic layers were combined and concentratedunder reduced pressure to give a brownish-black foamy semi-solid. Themixture was split in two equal portions, and each was purified by flashsilica gel chromatography using a mixture of methanol in ethyl acetate(5% to pack, 5% to load, 5% and 10% to run). The combined fractionsprovided 3.78 g (12.7%) of the product as a dark yellow solid (HPLCAP>99%).

The crude amount of A228.4 was 25.1 g (85%) as a light-brown solid. Thecompound (21.3 g) was dissolved in isopropyl alcohol (100 mL) and ˜4-5mL of methanol with sonication to give a dark, homogeneous solution.Within a minute of dissolving, the product began to crystallize out ofsolution. The mixture was stirred at room temperature overnight andfiltered through a 600 mL fritted funnel (medium porosity). The columnedmaterial (3.78 g) was recrystallized in a similar manner. The resultingsolids were washed with isopropyl alcohol and were dried well underreduced pressure to give 19.6 g of A228.4 (pale yellow). The black,homogenous filtrates were combined and concentrated under reducedpressure to give a brown solid (HPCL AP>98%) The compound. had an HPLCretention time=2.21 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.;Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O,and 0.1% TFA) and a LC/MS M(−Boc)⁺¹=380.26. ¹H NMR (500 MHz, DMSO-d₆) δppm 1.31 (s, 9H) 3.20 (s, 3H) 3.36 (s, 3H) 3.90 (s, 2H) 4.03 (s, 3H)4.41 (d, J=6.05 Hz, 2H) 6.20 (s, 2H) 7.24 (d, J=7.70 Hz, 1H) 7.65 (d,J=7.70 Hz, 1H) 7.80 (t, J=7.84 Hz, 1H) 7.97 (s, 1H) 8.42 (t, J=6.05 Hz,1H).

A228.5: tert-Butyl7-(6-((2-methoxyacetamido)methyl)pyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

To a 250 mL round bottom flask under nitrogen containing the acetyleneintermediate (10.0 g, 20.9 mmol) was added anhydrous dimethylacetamide(100 mL) via cannula without stirring. An outlet needle was added, andthe mixture was flushed with a stream of nitrogen for 1 min. The mixturewas then sonicated until the solution became homogeneous (˜0.5-1 min).An outlet needle was added, and reaction mixture was stirred under astream of nitrogen for 20 min at room temperature and was then immersedin an oil bath at 85° C. After 5 min, the outlet was removed, and thehomogenous mixture was stirred at 85° C., under a positive pressure ofnitrogen, for an additional 10 min to allow for complete equilibration.Potassium tert-butoxide (22.9 mL, 22.9 mmol, 1.1 equiv.) was added over15-30 sec via syringe. After 15 min, a second 1.1 equivalents (22.9 mL,22.9 mmol) was added, and the reaction mixture was stirred for 15 min,during which time the product precipitated out of solution. The reactionmixture was complete by TLC and was allowed to cool to room temperature.The mixture was cooled with an ice bath and quenched slowly with 20 mLof water to give a homogeneous solution which was transferred to a 1 Lseparatory funnel with an additional 80 mL of water. The aqueous mixturewas extracted with 300 mL of dichloromethane. The aqueous layer wasre-extracted with 3×100 mL of dichloromethane, and the organic layerswere combined and dried over anhydrous sodium sulfate. Concentrationunder reduced pressure followed by purification by flash silica gelchromatography using a mixture of methanol in dichloromethane (2%-5%)afforded 8.70 g (87%) of A228.5 as a pale yellow solid ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.30 (s, 9H) 3.30 (s, 3H) 3.38 (s, 3H) 3.94-3.96 (m, 2H)4.10-4.12 (m, 3H) 4.49 (d, J=5.77 Hz, 2H) 7.17 (d, J=7.70 Hz, 1H) 7.53(d, J=1.92 Hz, 1H) 7.83 (t, J=7.70 Hz, 1H) 7.89-7.92 (m, 1H) 8.14 (s,1H) 8.53 (t, J=5.91 Hz, 1H) 12.38 (d, J=1.92 Hz, 1H) (The productmixture contained ˜8% of A228).

A228.6:N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2-methoxy-acetamide

A solution of A228.5 (0.781 g, 1.63 mmol) in trifluoroacetic acid (10mL) was stirred at room temperature for 10 min. The reaction mixture wasconcentrated under reduced pressure, and the residue was diluted withdichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate (2×), and dried over anhydrous sodium sulfate. Concentrationunder reduced pressure afforded a quantitative yield of the product as ayellow solid. The material was triturated with methanol and filteredunder reduced pressure to give 0.532 g (91%) of A228 as a yellow solidMP 263° C. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.98 (d, J=4.95 Hz, 3H) 3.37(s, 3H) 3.94 (s, 2H) 4.02 (s, 3H) 4.44 (d, J=5.77 Hz, 2H) 6.67 (q,J=4.58 Hz, 1H) 7.01 (d, J=7.15 Hz, 1H) 7.29 (d, J=2.20 Hz, 1H) 7.68-7.74(m, 2H) 7.90 (s, 1H) 8.53 (t, J=5.77 Hz, 1H) 11.71 (s, 1H)

Alternate Preparation of A228

To a 250 mL round bottom flask containing A228.5 (16.0 g, 33.4 mmol)cooled in an ice-water bath was added trifluoroacetic acid (100 mL)slowly. After the addition was complete, the ice bath was removed, andthe homogeneous reaction mixture was stirred for 20 min. By HPLCanalysis, the reaction was complete. The reaction mixture wasconcentrated until the total volume was 61 g, a stir bar was added, andthe residue was cooled with an ice-water bath. To the stirring mixturewas added a 1:1 solution of ammonium hydroxide in water slowly. Once apH between 9-10 was achieved (˜160 mL of the 1:1 ammoniumhydroxide/water solution), the product precipitated out of solution. Themixture was stirred at room temperature for 45 min, filtered through afritted funnel (350 mL, medium porosity) with additional 1:1 ammoniumhydroxide/water solution (100 mL), and washed with the 1:1 ammoniumhydroxide/water solution (2×100 mL). The resulting off-white cake wasair dried overnight. The solid was transferred to a 1 L round bottomflask, diluted with methanol (˜500 mL), sonicated for 15 minutes, andconcentrated under reduced pressure. During the sonication procedure,the suspension changed from off-white to yellow in color. This sequencewas repeated two additional times. The resulting solid was diluted withmethanol (˜100 mL), filtered under reduced pressure, washed withmethanol (˜50 mL), and dried well under reduced pressure to give 12.0 g(95%) of A228 as a yellow solid.

Alternate Preparation of A228

To a 2000 mL 3-neck round bottom flask equipped with a mechanic stirrerunder nitrogen was charged with A228-methanesulfonic acid salt (67 g)and H₂O (670 mL). To this solution at 0° C. was added aqueous NH₄OH (7N,134 mL) drop wise over a period of 30 minutes. During theneutralization, the color was changed from orange to yellow then tocolorless. The solution was stirred for addition 90 minutes at 0° C. andthe solid was formed. The slurry was filtered and the solid was washedwith H₂O (2×150 mL), dried in vacuo at 45° C. for 48 hours to A228 as alight yellow solid (33.2 g of product which was 99.7% pure by HPLC).

The structure was confirmed by single crystal x-ray structure describedin Table 1 and shown in FIG. 1. TABLE 1 Structure and Properties ofCrystal Form Solvent Solvent dcalc Form Sites for Z′ %(w/w) Hot Stage (°C.) Z′ Vm sg g/cc T(° C.) R N-1 None 0.0 265-280 (m) 1 460 P2₁/c 1.37025 .055A228 Mono-HCl Salt

To a homogenous solution of A228 (2.43 g, 6.40 mmol) in dichloromethane(80 mL) and anhydrous methanol (20 mL) was added a 4M solution ofhydrochloric acid in dioxane (1.76 mL, 7.04 mmol) at room temperature.The reaction mixture immediately turned orange and gradually becamecloudy. After 15 min, the reaction mixture was concentrated to drynessunder reduced pressure, during which time the salt precipitated out ofsolution as a yellow solid. The residue was diluted with methanol(˜75-100 mL), and the suspension was sonicated for 5 min and then gentlyheated with a heat gun for and additional 5 min. A stir bar was added,and the suspension was stirred overnight. The precipitate was collectedby vacuum filtration, washed with methanol, and dried well under reducedpressure to give 2.41 g (90%) of A228 HCl salt as a yellow solid. Thecompound had an HPLC retention time=1.87 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min; Solvent A=10% MeOH, 90% H₂O, 0.1% TFA; SolventB=90% MeOH, 10% H₂O, 0.1% TFA) and a LC/MS M⁺¹=380.25. MP=295° C.

A228—Monohydrate

A228 (200 mg) was suspended in methanol (5 mL) and heated in a bathmaintained at 70° C., at which point the solution became homogenious.The reaction mixture was diluted with water (30 mL) and heated at 120°C. for 2.5 h. The mixture was allowed to cool to room temperature andfiltered. The product was air dried to yield 150 mg (72%) ofA228-monohydrate. MP ˜105-140° C. (dhyd) 259-262° C. (dec).

A228—Methanesulfonic Acid Salt

To a 2000 mL 3-neck round bottom flask equipped with a mechanic stirrerunder nitrogen containing A228.5 (45.5 g, 0.0938 mol) was added DCM (450mL). The mixture was heated to 40° C. under nitrogen to obtain a clearsolution. Methanesulfonic acid (42 g, 0.437) was added drop wise via anaddition funnel over a period of 20 minutes at this temperature. Afterthe mixture was stirred for additional 45 minutes, MTBE (300 mL) wasadded and the slurry was cooled to room temperature then to 4° C. andstirred at this temperature for 30 minutes. The slurry was filtered andthe solid was collected, washed with 1/1 DCM/MTBE (2×100 mL). The solidwas dried in vacuo at 45° C. for 12 hours to give A228 methane sulfonicacid salt as a yellow solid (67.3 g of product which was 99.7% pure byHPLC). ¹H NMR (500 MHz, DMSO-d₆) δ 12.16 (bs, 1H), 8.53 (t, J=6.05 Hz,1H), 8.48 (bs, 1H), 7.89 (m, 2H), 7.61 (s, 1H), 7.19 (d, J=7.4 Hz, 1H),4.51 (d, J=5.75 Hz, 2H), 4.13 (s, 3H), 3.97 (s, 2H), 3.37 (s, 3H), 3.12(s, 3H), 2.43 (s, 12H), LRMS (M+H)⁺: 380.33.

Example A246N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N-methyl-acetamide

A246.1: tert-Butyl methyl(1-methyl-7-(6-((N-methylacetamido)methyl)pyridin-2-yl)-1,6-dihydro-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl)carbamate

To a solution of A214 (0.780 g, 1.74 mmol) in anhydrous tetrahydrofuran(40 mL) at room temperature was added a sodium hydride (0.277 g, 6.94mmol, 60% in mineral oil). The resulting suspension was stirred for 15min. Iodomethane (0.12 mL, 1.91 mmol) was added, and the reactionmixture was stirred for 20 min. The reaction was complete by HPLC,quenched with a saturated aqueous solution of ammonium chloride, and thesolvent was remove under reduced pressure. The residue was diluted withdichloromethane, washed with a saturated aqueous solution of ammoniumchloride, and dried over anhydrous sodium sulfate. Concentration underreduced pressure followed by purification by flash silica gelchromatography using a 5% mixture of methanol in dichloromethaneprovided 0.685 (85%) of A246.1 as a pale yellow solid. The compound hadan HPLC retention time=2.30 min. (Column: Chromolith SpeedROD 4.6×50mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90%MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=464.34.

A246.2:N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N-methyl-acetamide

A solution of A246.1 (0.153 g, 0.330 mmol) in trifluoroacetic acid (5mL) at room temperature was stirred for 10 min. The trifluoroacetic acidwas remove under reduced pressure, and the residue was diluted withdichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate, and dried over anhydrous sodium sulfate. Concentrationunder reduced pressure afforded 0.119 g (99%) of A246 as a yellow solid.The compound had an HPLC retention time=1.93 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA;Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=364.38.

Example A2471,6-dihydro-N,1-dimethyl-7-[6-[(methylamino)methyl]-2-pyridinyl]-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A mixture of A246.1 (0.532 g, 1.15 mmol), absolute ethanol (10 mL), andconcentrated hydrochloric acid (10 mL) was stirred at 80° C. overnight.The reaction mixture was concentrated to dryness and dried well underreduced pressure to give a quantitative yield of the tris-hydrochloridesalt of A247 as a light brown solid. The salt was diluted withdichloromethane, neutralized with a saturated aqueous solution of sodiumbicarbonate, and dried over anhydrous sodium sulfate. Concentrationunder reduce pressure afforded 0.328 g (89%) of A247 as a light yellowsolid. The compound had an HPLC retention time=1.81 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=322.34. ¹H NMR (500 MHz, CDCl₃) δ ppm 2.00 (brs, 1H) 2.55 (s, 3H)3.19 (d, J=4.95 Hz, 3H) 3.87 (s, 2H) 4.04 (s, 3H) 5.51 (d, J=4.95 Hz,1H) 7.00 (s, 1H) 7.01 (d, J=7.70 Hz, 1H) 7.49-7.53 (m, 1H) 7.55-7.62 (m,2H) 9.93 (s, 1H)

Example A248N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2-methoxy-N-methyl-acetamide

To a mixture of A247 (0.032 g, 99.6 μmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.029 g,0.149 mmol), 1-hydroxybenzotriazole (0.020 g, 0.149 mmol), anddiisopropylethylamine (0.104 mL, 0.598 mmol) in anhydrousdimethylformamide (2 mL) was added methoxyacetic acid (0.012 mL, 0.149mmol). The homogeneous reaction mixture was heated at 75° C. for 15 min.The solvent was removed under reduced pressure, and the residue wasdiluted with dichloromethane, washed with a saturated aqueous solutionof sodium bicarbonate, and dried over anhydrous sodium sulfate.Concentration under reduced pressure followed by purification bypreparative HPLC afforded 0.023 g (59%) of A248 as a light-orange solid.The compound had an HPLC retention time=1.94 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA;Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=394.43.

Examples A249-A262

Examples A249-A262 were prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of either a carboxylic acid in dimethylformamide (DMF)(0.038mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol inDMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq) or an isocyanate or sulfonylchloride reagent with pyridine insimilar molar ratio to the carboxylic acid reagent. The reactor wasagitated for 10 minutes via orbital shaker. Then 150 uL of a solution of0.2 molar amine in DMF (0.03 mmol; 1 eq) and diisopropylethylamine(0.150; 5 eq) was added to each reactor well and the reactor wasagitated for 16 hours at 65° C. The library was dried via centrifugalevaporation and BOC groups were removed by adding 600 uL of a 30% byvolume solution of trifluoroacetic acid (TFA) in dichloromethane (DCM)to each reactor (that had a BOC group) and the reactor was agitated for2 hours. The library was dried via centrifugal evaporation and wasdissolved in 600 uL of DMF and 600 uL of methanol (MeOH). The entirecontents for each reactor were transferred to an STR plate was waspurified by standard preparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column) utilizingmass-directed fractionation. The purified sample was reconstituted in1:1/MeOH:DCE, transferred to a tared 2.5 mL plastic microtube, dried viacentrifugal evaporation and weighed. The final product was analyzed byHPLC-MS (H₂O/MeOH/0.1% TFA). Compounds were isolated as trifluoroacetatesalts. Examples prepared by this method are described in Table A9. TABLEA9

HPLC Retention MS Ex. R Name (min) Reported A249

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-ethoxy-N-methyl-acetamide 2.13 409.35 A250

(alphaS)-N-[[6-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-alpha- methoxy-N-methylbenzeneacetamide 2.48 470.32 A251

(alphaR)-N-[[6-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-alpha- methoxy-N-methylbenzeneacetamide 2.48 470.32 A252

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-1- hydroxy-N-methyl-cyclopropanecarboxamide 2.08 406.31 A253

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2-hydroxy-N,2-dimethyl- propanamide 2.07 408.32 A254

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]tetrahydro-N-methyl-3-furancarboxamide 2.04 420.31 A255

(R)N-[[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2- pyridinyl]methyl]tetrahydro-N-methyl-2- furancarboxamide 2.15 420.31 A256

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2- pyridinyl]methyl]tetrahydro-N-methyl-2- furancarboxamide 2.15 420.31 A257

(2R)-N-[[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-2- methoxy-N-methylpropanamide 2.07 408.31 A258

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N- methyl-propanamide2.15 378.32 A259

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N-methyl-6-(trifluoromethyl)-3- pyridinecarboxamide 2.59 495.21 A260

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-3- methoxy-N-methyl-propanamide 2.09 408.31 A261

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N- methyl-pentanamide2.58 406.36 A262

N-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N- methyl-butanamide2.36 392.38

Alternate Preparation Example A252N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-1-hydroxy-N-methyl-cyclopropanecarboxamide

To a mixture of A247 (0.025 g, 76.6 μmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.016 g,0.115 mmol), 1-hydroxybenzotriazole (0.022 g, 0.115 mmol), anddiisopropylethylamine (0.040 mL, 0.230 mmol) in anhydrousdimethylformamide (3 mL) was added 1-hydroxy-1-cyclopropylcarboxylicacid (0.012 mL, 0.115 mmol). The homogeneous reaction mixture was heatedat 85° C. for 15 min. The solvent was removed under reduced pressure,and the residue was diluted with dichloromethane, washed with asaturated aqueous solution of sodium bicarbonate, and dried overanhydrous sodium sulfate. Concentration under pressure followed bypurification by preparative HPLC afforded 0.016 g (52%) of A252 as ayellow solid. The compound had an HPLC retention time=1.97 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=406.38.

Alternate Preparation of A253N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2-hydroxy-N,2-dimethyl-propanamide

To a mixture of A247 (0.025 g, 76.6 μmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.016 g,0.115 mmol), 1-hydroxybenzotriazole (0.022 g, 0.115 mmol), anddiisopropylethylamine (0.040 mL, 0.230 mmol) in anhydrousdimethylformamide (3 mL) was added 1-hydroxy-1-cyclopropylcarboxylicacid (0.012 mL, 0.115 mmol). The homogeneous reaction mixture was heatedat 85° C. for 15 min. The solvent was removed under reduced pressure,and the residue was diluted with dichloromethane, washed with asaturated aqueous solution of sodium bicarbonate, and dried overanhydrous sodium sulfate. Concentration under pressure followed bypurification by preparative HPLC afforded 0.013 g (42%) of A253 as ayellow solid. The compound had an HPLC retention time=1.97 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=408.38.

Example A263 and Example A263a5-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-fluoro-benzonitrileand7-[3-(aminomethyl)-4-fluorophenyl]-1,6-dihydro-N,1-dimethyl-imidazol-4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A263.1: tert-Butyl6-amino-7-(2-(3-cyano-4-fluorophenyl)ethyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A263.1 was prepared in a similar manner as example 2.3 using A1.12 and3-ethynyl-4-fluorobenzonitrile. HPLC: 82%, retention time: 3.236 minute(condition A). LC/MS (M+H)⁺=421.4

A263.2: tert-butyl7-((3-cyano-4-fluorophenyl)ethynyl)-1-methyl-6-(2,2,2-trifluoroacetamido)-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

To a solution of A263.1 (60 mg, 0.14 mmol) and triethylamine (65 mg,0.65 mmol) in THF (2 ml) was added trifluoroacetic anhydride (107 mg,0.51 mmol) dropwise at RT and stirred for 20 minutes. The reactionmixture was concentrated and purified on silica gel column withHexane/EtOAc (2/3, Isco) to yield A263.2 (51.5 mg, 70%). HPLC: 82%,retention time: 3.506 minute (condition A). LC/MS (M+H)⁺=517.

A263.3: tert-butyl7-(3-cyano-4-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of A263.2 (10 mg, 0.019 mmol), K₂CO₃ (2.68 mg, 0.019 mmol)and tetrakis(triphenylphosphine)Palladium(0) (1.4 mg, 0.0012 mmol) indimethyl acetamide (0.5 ml) was heated to 90° C. for 16 hrs. Thereaction mixture was concentrated and purified on prep. HPLC (conditionG) to yield A263.3 (5.7 mg, 70%). HPLC: 99%, retention time: 3.220minute (condition A). LC/MS (M+H)⁺=421.4.

A263.4:5-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-fluoro-benzonitrile

Example A263 was prepared in a similar manner as step A2.4. HPLC: 90%,retention time: 2.407 minute (condition A). LC/MS (M+H)⁺=321.3, (400MHz, DMSO-d₆) δ ppm 8.34 (1H, dd, J=5.85, 2.29 Hz), 8.12-8.24 (1H, m),7.48-7.66 (2H, m), 7.35 (1H, s), 4.04 (3H, s), 2.99 (3H, s).

A263.5: tert-butyl7-(3-aminomethyl-4-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

Raney Ni (500 mg) was rinsed with ethanol and A263.3 (890 mg, 2.12 mmol)in ethanol (25 ml) was added. The reaction mixture was saturated withNH₃ gas and then it was stirred under hydrogen balloon at RT for 12 hrs.Filtration and concentration to yield a product A263.5 (857 mg, 96%).HPLC: 98%, retention time: 2.108 minute (condition A). LC/MS(M+H)⁺=425.4.

A263.6:7-[3-(aminomethyl)-4-fluorophenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A263a was prepared in a similar manner to Similar method as example A3.HPLC: 93%, retention time: 1.483 minute (condition A). LC/MS(M+H)⁺=325.3, ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.96 (1H, s), 7.75-7.82 (1H,m), 7.41-7.58 (1H, m), 7.21 (1H, t, J=9.41 Hz), 7.02 (1H, s), 4.16 (2H,s), 4.03 (3H, s), 3.12 (3H, s).

Examples A264-A292

Examples A264-A292 were prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of either a carboxylic acid in dimethylformamide (DMF)(0.038mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol inDMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq) or an isocyanate or sulfonylchloride reagent with pyridine insimilar molar ratio to the carboxylic acid reagent. The reactor wasagitated for 10 minutes via orbital shaker. Then 150 uL of a solution of0.2 molar amine in DMF (0.03 mmol; 1 eq) and diisopropylethylamine(0.150; 5 eq) was added to each reactor well and the reactor wasagitated for 16 hours at 65° C. The library was dried via centrifugalevaporation and BOC groups were removed by adding 600 uL of a 30% byvolume solution of trifluoroacetic acid (TFA) in dichloromethane (DCM)to each reactor (that had a BOC group) and the reactor was agitated for2 hours. The library was dried via centrifugal evaporation and wasdissolved in 600 uL of DMF and 600 uL of methanol (MeOH). The entirecontents for each reactor were transferred to an STR plate was waspurified by standard preparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column) utilizingmass-directed fractionation. The purified sample was reconstituted in1:1N/MeOH:DCE, transferred to a tared 2.5 mL plastic microtube, driedvia centrifugal evaporation and weighed. The final product was analyzedby HPLC-MS (H₂O/MeOH/0.1% TFA). Compounds were isolated astrifluoroacetate salts. Examples prepared by this method are describedin Table A10. TABLE A10

HPLC Retention MS Ex. R Name (min) Reported A264

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-2-hydroxy-acetamide 2.14 383.31 A265

(2S)-N-[[5-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3 -b]pyridin-7-yl]- 2-fluorophenyl]methyl]-, 2-pyrrolidinecarboxamide 2.01 422.33 A266

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-2-hydroxy-2-methyl- propanamide 2.33 411.31 A267

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-hydroxy-butanamide 2.25 411.32 A268

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-2-methoxy-acetamide 2.33 397.34 A269

2-cyano-N-[[5-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]- acetamide 2.20392.31 A270 CH₃— N-[[5-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-2-fluorophenyl]methyl]- acetamide 2.25 367.32 A271

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-1- hydroxy-cyclopropanecarboxamide 2.29 409.31 A272

1-cyano-N-[[5-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-cyclopropanecarboxamide 2.46 418.31 A273

(2S)-2-amino-N-[[5-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-hydroxypropanamide 1.91 412.31 A274

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-methoxy-propanamide 2.31 411.31 A275 CH₃CH₂—N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]- propanamide 2.38381.32 A276

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-2-(2-methoxyethoxy)-acetamide 2.43 441.31 A277

(2R)-N-[[5-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]2-pyrrolidinecarboxamide 2.02 422.32 A278 CF₃CH₂—N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3,3,3-trifluoro-propanamide 2.53 435.26 A279

(2S,4R)-N-[[5-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-4- hydroxy-2-pyrrolidinecarboxamide 1.96 438.31 A280

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-cyclopropanecarboxamide 2.46 393.34 A281

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-4-pyridinecarboxamide 2.17 430.29 A282

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-2-pyridinecarboxamide 2.95 430.30 A283

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-2-fluorophenyl]methyl]-2,2- dimethyl-propanamide 2.72 409.35 A284

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-pyridinecarboxamide 2.21 430.29 A285

(2S)-2-amino-N-[[5-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-(phenylmethoxy)propanamide 2.45 502.33 A286

(2S,4R)-N-[[5-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-4-(phenylmethoxy)2- pyrrolidinecarboxamide 2.47 528.33 A287

(2S)-N-[[5-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3- hydroxy-2-(methylamino)propanamide 1.93 426.33 A288

(3S)-N-[[5-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-hydroxybutanamide 2.26 411.32 A289

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-hydroxy-3-methyl- butanamide 2.42 425.31 A290

(2S,3R)-2-amino-N-[[5-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-2-fluorophenyl]methyl]-3- methoxybutanamide 2.09 440.31 A291

N-[[5-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-2-oxo-1-pyrrolidinebutanamide 2.37 478.30 A292

(2S)-2-amino-N-[[5-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-fluorophenyl]methyl]-3-methoxypropanamide 2.02 426.31

Example A2937-[3-(aminomethyl)-5-fluorophenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A293.1: 3-fluoro-5-((trimethylsilyl)ethynyl)benzonitrile

A solution of 3-bromo-5-fluorobenzonitrile (2.5 g, 12.5 mmol),(trimethylsilyl)acetylene (2.86 ml, 20 mmol),bis(acetate)bis(triphenylphoshpino) Palladium(II) (936 mg, 1.25 mmol)and triethylamine (35 ml) in toluene (35 ml) was 15 degassed by bubblingnitrogen through the solution and then stirred at 95° C. for 30 minutes.Filtration and concentration to yield a crude product. It was dilutedwith EtOAc (150 ml). The organic phase was washed with saturated NaHCO₃solution (50 ml), brine (50 ml) and the organic layer was dried oversodium sulfate. Filtration and concentration to yield a product A293.1(2.4 g, 88%). HPLC: 95%, retention time: 4.05 minute (condition A).LC/MS (M+H)⁺=218.2.

A293.2: 3-ethynyl-5-fluorobenzonitrile

A solution of A293.1 (2.3 g, 10.7 mmol) and KOH (55 mg, 0.98 mmol in0.55 ml of water) in THF (20 ml) was stirred at RT for 30 minutes. Thereaction mixture was concentrated to yield a crude product. It wasdiluted with EtOAc (100 ml). The organic phase was washed with water (20ml), brine (20 ml) and the organic layer was dried over sodium sulfate.Filtration and concentration to yield a crude product. It was purifiedon silica gel column with Hexane/EtOAc (Isco) to yield A293.2 (1.35 g,87%). HPLC: 72%, retention time: 2.818 minute (condition A). LC/MS(M+H)⁺=146.1.

A293.3: tert-butyl6-amino-7-((3-cyano-5-fluorophenyl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

was prepared in a similar manner to example 2.3 using A293.2 as theacetylene.

HPLC: 82%, retention time: 3.281 minute (condition A). LC/MS(M+H)⁺=421.3.

A293.4: tert-butyl7-((3-cyano-5-fluorophenyl)ethynyl)-1-methyl-6-(2,2,2-trifluoroacetamido)-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A293.4 was prepared in a similar manner as example A263.2

HPLC: 80%, retention time: 3.486 minute (condition A). LC/MS(M+H)⁺=517.3.

A293.4: tert-butyl7-(3-cyano-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A293.4 was prepared similar to the procedure described for A263.3 HPLC:99%, retention time: 3.246 minute (condition A). LC/MS (M+H)⁺=421,¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.34 (1H, s), 8.14-8.21 (2H, m),7.70-7.77 (2H, m), 4.10 (3H, s), 3.30 (3H, s), 1.30 (9H, s).

A293.5: tert-butyl7-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A293 was prepared in a similar manner to A3.1

HPLC: 92%, retention time: 2.098 minute (condition A). LC/MS(M+H)⁺=425.3, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.01 (1H, s), 7.61 (1H, s),7.45 (1H, d, J=9.66 Hz), 7.24 (1H, s), 7.00 (1H, d, J=9.66 Hz), 4.09(3H, s), 3.82 (2H, s), 3.29 (3H, s), 1.28 (9H, s).

A293.6: 7-[3-(aminomethyl)-5-fluorophenyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A293a was prepared in a similar manner as step A3.2. HPLC: >98%,retention time: 1.807 minute (condition B). LC/MS (M+H)⁺=325.3, ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.01 (1H, s), 7.58 (1H, s), 7.53 (1H, d, J=10.17Hz), 7.16 (1H, s), 7.03 (1H, d, J=8.65 Hz), 4.08-4.15 (2H, m), 4.04 (3H,s), 3.14 (3H, s).

Examples A294-A313

Examples A294-A313 were prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of either a carboxylic acid in dimethylformamide (DMF)(0.038mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol inDMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq) or an isocyanate or sulfonylchloride reagent with pyridine insimilar molar ratio to the carboxylic acid reagent. The reactor wasagitated for 10 minutes via orbital shaker. Then 150 uL of a solution of0.2 molar amine in DMF (0.03 mmol; 1 eq) and diisopropylethylamine(0.150; 5 eq) was added to each reactor well and the reactor wasagitated for 16 hours at 65° C. The library was dried via centrifugalevaporation and BOC groups were removed by adding 600 uL of a 30% byvolume solution of trifluoroacetic acid (TFA) in dichloromethane (DCM)to each reactor (that had a BOC group) and the reactor was agitated for2 hours. The library was dried via centrifugal evaporation and wasdissolved in 600 uL of DMF and 600 uL of methanol (MeOH). The entirecontents for each reactor were transferred to an STR plate was waspurified by standard preparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column) utilizingmass-directed fractionation. The purified sample was reconstituted in1:1/MeOH:DCE, transferred to a tared 2.5 mL plastic microtube, dried viacentrifugal evaporation and weighed. The final product was analyzed byHPLC-MS (H₂O/MeOH/0.1% TFA). Compounds were isolated as trifluoroacetatesalts. Examples prepared by this method are described in Table A11.TABLE A11

HPLC Retention MS Ex. R Name (min) Reported A294

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-cyclopropanecarboxamide 2.48 393.32 A295

2-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]- acetamide 2.26392.31 A296 CH₃CH₂— N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]- propanamide 2.40 381.31 A297

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-2,2-dimethyl-propanamide 2.71 409.32 A298

2-(acetylamino)-N-[[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]- acetamide 2.11 424.31 A299

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-2-methoxy-acetamide 2.34 397.30 A300 HOCH₂— N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]-2- hydroxy-acetamide 2.15 383.30 A301

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-2-hydroxy-2-methyl- propanamide 2.32 411.30 A302

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-1- hydroxy-cyclopropanecarboxamide 2.30 409.30 A303

(2S)-1-acetyl-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-2-pyrrolidinecarboxamide 2.29 464.30 A304 CH₃—N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]- acetamide 2.25367.30 A305

(2S)-N-[[3-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-2-pyrrolidinecarboxamide 2.03 422.31 A306

(2S,4R)-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-4-(phenylmethoxy)-2- pyrrolidinecarboxamide 2.50 528.27 A307

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-2-(2-methoxyethoxy)-acetamide 2.43 411.31 A308

(2S,4R)-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-4- hydroxy-2-pyrrolinecarboxamide 1.96 348.30 A309

(2R)-1-acetyl-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-2-pyrrolidinecarboxamide 2.27 464.31 A310 CF₃CH₂—N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-3,3,3-trifluoro-propanamide 2.55 435.25 A311

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-4-methyl-1,2,3-thiadiazole-5- carboxamide 2.68 451.21 A312

1-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-cyclopropanecarboxamide 2.51 418.24 A313

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-3-morpholinecarboxamide 1.99 438.29

Example A3141,6-dihydro-N,1-dimethyl-7-[3-[(methylamino)methyl]phenyl]-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-aminehydrochloride salt

A314.1: Methyl-(3-trimethylsilanylethynyl-benzyl)-carbamic acidtert-butyl ester

TMS-Acetylene (2.2 mL, 15.0 mmol) was added dropwise to commerciallyavailable tert-butyl 3-bromobenzyl(methyl)carbamate (3.0 g, 10 mmol),CuI (100 mg, 0.5 mmol) and palladium dichlorobistriphenylphosphine (210mg, 0.3 mmol) in triethylamine (30 mL) at room temperature under anitrogen atmosphere. The reaction mixture was heated to 70° C. for 12hrs before cooling to room temperature and evaporating in vacuo. Theresidue was triturated with diethyl ether (30 mL), filtered and thefiltrate evaporated in vacuo and purified by column chromatography (5%ethyl acetate in hexane) to yield A314.1 (3.2 g, 100%) as a brown oil.HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.34 min,M+Na⁺=340.34

A314.2: (3-Ethynyl-benzyl)-methyl-carbamic acid tert-butyl ester

Potassium hydroxide solution (1 pellet dissolved in 1 mL of water) wasadded in one portion to A314.1 (3.2 g) in anhydrous methanol (50 mL).After stirring at room temperature for 2 hrs, the reaction was quenchedby the addition of water (25 mL), and the mixture was extracted withhexane (3×100 mL). The combined organics were dried (MgSO4), evaporatedin vacuo and purified by column chromatography ((5% ethyl acetate inhexane) to yield A314.2 as an oil (2.54 g, 100%). HPLC YMC S5-4.6×33 mm(2 min gradient): ret. Time=1.41 min, M+H⁺=210.24

A314.3(6-Amino-7-{3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)-methyl-carbamicacid tert-butyl ester

A1.12 (1.5 g, 3.72 mmol), dichlorobis(triphenylphosphine)palladium (174mg, 0.25 mmol), A314.2 (1.14 g, 4.65 mmol) and triethylamine (12 mL)were each added to N,N-dimethylformamide (6 mL) and nitrogen bubbledthrough the resulting mixture for 5 min. The reaction mixture was heatedat 90° C. for 12 hrs under a nitrogen atmosphere before cooling to roomtemperature and evaporating the solvent in vacuo. The residue waspurified by silica gel column chromatography using 1:1 ethylacetate:hexane as eluent to provide 1.45 g (75%) of A314.3. HPLC YMC S-54.6×33 mm (2 min grad): retention time 1.98 min, M+H⁺=521.46

A314.4:[7-{3-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-phenylethynyl}-1-methyl-6-(2,2,2-trifluoro-acetylamino)-1H-imidazo[4,5-c]pyridin-4-yl]-methyl-carbamicacid tert-butyl ester

Trifluoroacetic anhydride (0.77 mL, 5.54 mmol) was added dropwise over 5min to a cooled (0 C) solution of A314.3 (1.44 g, 2.77 mmol) andtriethylamine (1.16 mL, 8.31 mmol) in THF (40 mL) under a nitrogenatmosphere. The cooling bath was removed after 10 min and the reactionmixture allowed to stir at room temperature for 1 hr before evaporatingin vacuo. The residue was taken up in dichloromethane (50 mL) and washedwith saturated sodium bicarbonated solution (25 mL). The organic layerwas separated and dried (MgSO4), then evaporated in vacuo to yield thecrude product A314.4 which was used immediately without furtherpurification (1.76 g). HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 2.08 min, M+H⁺=617.39.

A314.5: 1,6-dihydro-N,1-dimethyl-7-[3-[(N-methyl-tert-butyloxycrbonylamino)methyl]phenyl]-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-tert-butyloxycarbonylamine

Potassium carbonate (400 mg, 2.86 mmol) anddichlorobistriphenylphosphine (210 mg, 0.3 mmol) were each added in oneportion to a solution of A314.4 (1.76 g, 2.86 mmol) in dimethylacetamide(30 mL). at room temperature under a nitrogen atmosphere. The reactionwas heated to 120 C for 48 hrs before evaporating in vacuo. The residuewas partitioned between water (30 mL) and ethyl acetate (50 mL). Theseparated organic layer was dried (MgSO4), evaporated in vacuo andpurified by column chromatography using 2:1 ethyl acetate:hexane toyield A314.5 (1.3 g, 95%). HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.99 min, M+H⁺=521.42

A314.6:1,6-dihydro-N,1-dimethyl-7-[3-[(methylamino)methyl]phenyl]-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A314.5 (1.3 g, 2.5 mmol) was suspended in 4N HCl in dioxane (30 mL) andstirred at room temperature overnight. The reaction mixture wasevaporated in vacuo and the residue triturated with diethyl ether toyield A314 (568 mg, 58%). HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 1.10 min, M+H⁺=321.34. ¹H NMR (400 MHz, DMSO) δ 12.13 (s, 1H), 9.33(s, 1H), 8.06 (s, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.50 (t, J=8.6 Hz, 1H),7.40 (d, J=8.6 Hz, 1H), 7.29 (s, 1H), 4.22 (s, 3H), 2.96 (s, 3H), 2.51(s, 3H).

Example A315N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-3-methoxy-N-methyl-propanamide

EDC (135 mg, 1.07 mmol) was added in one portion to a mixture of3-methoxypropionic acid (42 mg, 0.41 mmol), HOBt (73 mg, 0.91 mmol) andDIPEA (0.5 mL) in anhydrous DMF (2 mL) and the resulting mixture wasallowed to stir at room temperature for 30 min before addition of theA314 (100 mg, 0.25 mmol). The mixture was heated to 70 C for 48 hrs in ascrew-capped vial before cooling to room temperature and evaporating invacuo. The residue was partitioned between ethyl acetate (5 mL) andwater (2 mL). The separated aqueous layer was extracted with ethylacetate (3×10 mL) and the combined organics dried (MgSO4), evaporated invacuo and purified by column chromatography (5% MeOH in EtOAc) to yieldA315 (62 mg). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.51min, M+H⁺=407.41.

Example A316N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-N-methyl-acetamide

Example A316 was prepared in a similar manner to A315. HPLC YMC S-54.6×33 mm (2 min grad): retention time 1.45 min, M+H⁺=363.42.

Example A317N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-N-methyl-methanesulfonamide

Methansulfonyl chloride (20 mg, 0.26 mmol) was added in one portion toA314 (192 mg, 0.23 mmol) and triethylamine (60 mg, 0.59 mmol) in THF (2mL). The reaction mixture was stirred at room temperature for 30minutes. The solvent was evaporated under reduced pressure and theresidue purified by preparatory reverse phase chromatography to yieldA317. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.50 min,M+H+=399.40.

Examples A318-A331

Examples A318-A331 were prepared by parallel synthesis according to thescheme shown below.

To an individual well in a Bohdan XT® reactor was added 150 uL of a 0.25M solution of either a carboxylic acid in dimethylformamide (DMF)(0.038mmol; 1.25 eq), 37.5 uL of a 1 M solution of 1-hydroxybenzotriazol inDMF (0.038 mmol, 1.25 equiv) and 150 uL of a 0.25 M solution ofN-(3-dimethylaminopropyl)-N-ethylcarbodiimide hychloride (0.038 mmol;1.25 eq) or an isocyanate or sulfonylchloride reagent with pyridine insimilar molar ratio to the carboxylic acid reagent. The reactor wasagitated for 10 minutes via orbital shaker. Then 150 uL of a solution of0.2 molar amine in DMF (0.03 mmol; 1 eq) and diisopropylethylamine(0.150; 5 eq) was added to each reactor well and the reactor wasagitated for 16 hours at 65° C. The library was dried via centrifugalevaporation and BOC groups were removed by adding 600 uL of a 30% byvolume solution of trifluoroacetic acid (TFA) in dichloromethane (DCM)to each reactor (that had a BOC group) and the reactor was agitated for2 hours. The library was dried via centrifugal evaporation and wasdissolved in 600 uL of DMF and 600 uL of methanol (MeOH). The entirecontents for each reactor were transferred to an STR plate was waspurified by standard preparative HPLC-MS (H₂O/MeOH/0.1% TFA, gradient35-90% MeOH over 15 min, 20×100 mm 5 μm YMC ODS-A column) utilizingmass-directed fractionation. The purified sample was reconstituted in1:1/MeOH:DCE, transferred to a tared 2.5 mL plastic microtube, dried viacentrifugal evaporation and weighed. The final product was analyzed byHPLC-MS (H₂O/MeOH/0.1% TFA). Compounds were isolated as trifluoroacetatesalts. Examples prepared by this method are described in Table A12.TABLE A12

HPLC Retention MS Ex. R Name (min) Reported A318

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-(2-methoxyethoxy)-N-methyl- acetamide 2.34 437.33 A319

1-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N-methyl-cyclopropanecarboxamide 2.49 414.34 A320

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-methoxy-N-methyl-acetamide 2.29 393.35 A321

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N,2,2-trimethyl-propanamide 2.86 405.38 A322 CH₃CH₂—N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazol[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N-methyl- propanamide 2.49377.34 A323

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N-methyl-cyclopropanecarboxamide 2.55 389.38 A324

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-1-hydroxy- N-methyl-cyclopropanecarboxamide 2.44 405.35 A325

2-(acetylamino)-N-[[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-N-methyl- acetamide 2.17 420.31 A326

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-yl]phenyl]methyl]-2-hydroxy- N,2-dimethyl-propanamide 2.42 407.38 A327CF₃CH₂— N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-3,3,3- trifluoro-N-methyl-propanamide 2.56 431.29 A328

(2R)-1-acetyl-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N-methyl-2-pyrrolidinecarboxamide 2.36 460.32 A329

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N,4-dimethyl-1,2,3-thiadiazole-5- carboxamide 2.53 447.31 A330

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-2-hydroxy-N-methyl-acetamide 2.15 379.35 A331

(2S)-1-acetyl-N-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl]phenyl]methyl]-N-methyl-2-pyrrolidinecarboxamide 2.36 460.32

Example A3323-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzyl4-isopropylpiperazine-1-carboxylate

A332.1: 2-(3-Iodo-benzyloxy)-tetrahydro-pyran

para-Toluenesulfonic acid (100 mg, cat.) was added in one portion to acooled solution (0 C) of 3-iodobenzyl alcohol (4.71 g, 0.02 mol) anddihydropyran (1.86 g, 0.022 mol) in dichloromethane (50 mL) under anitrogen atmosphere. The cooling bath was removed and the reactionmixture was allowed to warm to room temperature over 1 hr. Diethyl ether(100 mL) was then added followed by saturated sodium hydrogen carbonatesolution (100 mL). The organic layer was separated, dried (MgSO₄) andevaporated in vacuo to yield the crude product (6.59 g) A332.1, whichwas used immediately without further purification. HPLC YMC S-5 4.6×33mm (2 min grad): retention time 2.16 min, no M+H⁺ observed.

A332.2:Trimethyl-[3-(tetrahydro-pyran-2-yloxymethyl)-phenylethynyl]-silane

TMS-Acetylene (3.2 mL, 22.6 mmol) was added dropwise to A332.1 (6.59 g,20.6 mmol), CuI (200 mg, 1.0 mmol) and palladiumdichlorobistriphenylphosphine (1 g, 1.3 mmol) in triethylamine (5.5 mL)and anhydrous DMF (50 mL) at room temperature under a nitrogenatmosphere. The reaction mixture was stirred at room temperatureovernight before evaporating in vacuo. Diethyl ether (50 mL) was addedto the residue and the slurry filtered. The filtrate was evaporated invacuo to yield the crude product A332.2 which (8.2 g) which was usedimmediately without further purification. HPLC YMC S-5 4.6×33 mm (2 mingrad): retention time 2.38 min, no M+H⁺ observed.

A332.3: 2-(3-Ethynyl-benzyloxy)-tetrahydro-pyran

Potassium hydroxide solution (1 pellet dissolved in 1 mL of water) wasadded in one portion to A332.2 (8.2 g) in anhydrous methanol (50 mL).After stirring at room temperature for 2 hrs, the reaction was quenchedby the addition of water (25 mL), and the mixture was extracted withhexane (2×250 mL). The combined organics were dried (MgSO4), evaporatedin vacuo and purified by column chromatography (10% ethyl acetate inhexane) to yield A332.3 as an oil (2.43 g, 56% over 3 steps). HPLC YMCS-5 4.6×33 mm (2 min grad): retention time 1.93 min, no M+H⁺ observed.

A332.4:{6-Amino-1-methyl-7-[3-(tetrahydro-pyran-2-yloxymethyl)-phenylethynyl]-1H-imidazo[4,5-c]pyridin-4-yl}-methyl-carbamicacid tert-butyl ester

A1.12 (1.5 g, 3.72 mmol), dichlorobis(triphenylphosphine)palladium (174mg, 0.25 mmol), A332.3 (1.0 g, 4.65 mmol) and triethylamine (12 mL) wereeach added to N,N-dimethylformamide (6 mL) and nitrogen bubbled throughthe resulting mixture for 5 min. The reaction mixture was heated at 90°C. for 12 hrs under a nitrogen atmosphere before cooling to roomtemperature and evaporating the solvent in vacuo. Diethyl ether wasadded to the residue (20 mL) and filtered. The filtrate was evaporatedin vacuo purified by silica gel column chromatography using 1:1 ethylacetate:hexane as eluent to provide 1.62 g (89%) of A332.4. HPLC YMCS-54.6×33 mm (2 min grad): retention time 1.92 min, M+H⁺ (−THP)=492.45

A332.5:3-[1,6-dihydro-1-methyl-4-(N-methyl-tert-buyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-1-(tetrahydro-pyran-2-yloxymethyl)benzene

Potassium tert-butoxide (1.0M in THF, 3.3 mL, 3.3 mmol) was addeddropwise over 10 min to a solution of the A332.4 (1.62 g, 3.30 mmol) inDMA (15 mL) at room temperature under a nitrogen atmosphere. Thereaction was heated to 90° C. for 1 hr before cooling to roomtemperature and evaporating in vacuo. The residue was purified by columnchromatography using ethyl acetate as eluent to yield A332.5 (1.18 g,73%). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.90 min, M+H⁺(−THP)=492.45

A332.6:3-[1,6-dihydro-1-methyl-4-(N-methyl-tert-buyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-benzenemethanol

HCl (1.0N aqueous solution, 7.2 mL, 7.2 mmol) was added dropwise over 5min to a solution of A333.5 (1.18 g, 2.4 mmol) in THF (25 mL) at roomtemperature. The reaction mixture was stirred at room temperature for 10hrs before quenching with sodium hydroxide solution (2N, 3.6 mL). Themixture was extracted with ethyl acetate (2×50 mL), the combined organicextracts dried (MgSO4) and evaporated in vacuo to yielded A332.6 (1.04g) as a yellow solid which was used immediately in the next reactionwithout further purification. HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.74 min, M+H⁺=492.45

A332.7:[7-[3-[[[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]oxy]methyl]phenyl]-1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl]methyl-carbamicacid, 1,1-dimethylethyl ester

DSC (1 g, 3.85 mmol) was added in one portion to a solution of A332.8(1.04 g, 2.57 mmol) and triethylamine (1.1 mL, 7.7 mmol) in THF (40 mL)at room temperature under a nitrogen atmosphere. The reaction mixturewas heated to 40° C. for 5 hrs before evaporating in vacuo. The residuewas dissolved in dichloromethane (50 mL) and washed with 5% aqueoussodium hydrogen carbonate solution (50 mL) then water (50 mL). Theorganic layer was separated, dried (MgSO₄) and evaporated in vacuo toyield A332.7 (1.2 g) as a yellow solid which was used immediatelywithout further purification. HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.56 min, M+H⁺⁼549.34

A332.8:3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-dυpyrrolo[2,3-b]pyridin-7-yl)benzyl4-isopropylpiperazine-1-carboxylate

Dimethylamine (2.0M in THF, 1 mL, 2 mmol) was added in one portion tothe succinimide carbonate A333.7 (15 mg, 0.027 mmol). The reactionmixture was allowed to stir at room temperature in a screw capped vialfor 1 hr before the addition of 4N HCl in dioxane (2 mL) with continuedstirring for 2 h. The reaction mixture was evaporated in vacuo andpurified by preparative hplc to yield A332 (3.0 mg). HPLC YMC S-5 4.6×33mm (2 min grad): retention time 1.76 min, M+H⁺=379.37

Example A3333-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-benzenemethanol

HCl (4.0N in dioxane, 2.0 mL) was added in one portion to A332.6 (20 mg,0.0049 mol). The reaction mixture was stirred at room temperature for 1hr before evaporating in vacuo and triturating with diethyl ether (10mL) to yield A333 (9.12 mg) as a yellow solid. HPLC YMC S-5 4.6×33 mm (2min grad): retention time 1.22 min, M+H⁺=308.35. ¹H NMR (500 MHz, MeOD)δ 8.19, (s, 1H), 7.73 (s, 1H), 7.64 (d, J=7.7 hz, 1H), 7.41 (t, J=7.7hz, 1H), 7.30 (d, J=7.7 hz, 1H), 7.15 (s, 1H), 4.66 (s, 2H), 4.13 (s,3H) and 3.24 (s, 3H).

Examples A334-A390

Examples A334-A390 were prepared by parallel synthesis according to thescheme shown below.

TABLE A13

HPLC Retention MS Ex. R Name (min) Reported A334

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- methoxyethylcarbamate 2.49409.29 A335 CH₃NH— 3-(1-methyl-4- 2.45 365.25 (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)benzylmethyethylcarbamate A336

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl cyclopropylcarbamate 2.63 391.28A337

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 5-methyl-1,3,4-thiadiazol-2-ylcarbamate 2.75 449.19 A338

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl tert-butylcarbamate 2.94 407.29A339

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- fluorobenzylcarbamate 3.01459.22 A340

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- hydroxyethylcarbamate 2.31395.23 A341

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl bis(2- methoxyethyl)carbamate 2.77467.25 A342

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl isoxazol-3- ylcarbamate 2.60 418.21A343

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- isopropoxyethylcarbamate 2.82437.28 A344

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3-oxopiperazine-1- carboxylate 2.35434.24 A345

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4- (hydroxymethyl)piperidine-1-carboxylate 2.69 449.32 A346

(R)-3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- hydroxypyrrolidine-1-carboxylate 2.50 421.31 A347

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl methyl(1- methylpyrrolidin-3-yl)carbamate 2.20 448.33 A348

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4-acetylpiperazine- 1-carboxylate2.51 462.31 A349

2-((3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyloxy)carbonylamino) acetic acid 2.23450.35 A350

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- (dimethylamino)propyl(methyl)carbamate 2.23 450.35 A351

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- (dimethylamino)ethyl(methyl)carbamate 2.15 436.32 A352

(S)-3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- (methoxymethyl)pyrrolidine-1-carboxylate 2.93 449.32 A353

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl methyl(propyl)carbamate 3.04 407.33A354

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl diethylcarbamate 3.01 407.34 A355

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl ethyl(methyl)carbamate 2.85 393.33A356

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl methyl(phenethyl)carbamate 3.29469.32 A357

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl benzyl(methyl)carbamate 3.20 455.30A358

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl isopentylcarbamate 3.12 421.31 A359

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl phenethylcarbamate 3.10 455.30 A360

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- acetamidoethylcarbamate 2.32436.29 A361 EtNH— 3-(1-methyl-4- 2.57 379.31 (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)benzyl ethylcarbamateA362

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4- fluorobenzylcarbamate 3.00459.25 A363

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl isopropylcarbamate 2.73 393.31 A364

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl methyl(1- methylpiperidin-4-yl)carbamate 2.23 462.32 A365

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl pyridin-4- ylmethylcarbamate 2.12442.29 A366

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl pyridin-3- ylmethylcarbamate 2.14422.27 A367

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl pyridin-2- ylmethylcarbamate 2.14442.25 A368

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4-(2- hydroxyethyl)piperidine-1-carboxylate 2.82 463.32 A369

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- (hydroxymethyl)piperidine-1-carboxylate 2.74 449.32 A370

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl morpholine-4- carboxylate 2.64421.31 A371

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4-(2- hydroxyethyl)piperazine-1-carboxylate 2.10 464.31 A372

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4- methylpiperazine-1- carboxylate2.10 434.31 A373

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl pyrrolidine-1- carboxylate 2.91405.32 A374

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl benzyl(methyl)carbamate 2.96 485.29A375

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- hydroxyethyl(methyl)carbamate2.45 409.31 A376

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- cyanoethyl(methyl)carbamate 2.50418.31 A377

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4-phenylpiperazine- 1-carboxylate3.04 496.32 A378

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl sec-butylcarbamate 2.87 407.36 A379

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- fluorobenzylcarbamate 2.99459.28 A380

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl isobutylcarbamate 2.92 407.36 A381

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- hydroxypiperidine-1- carboxylate2.59 435.32 A382

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl cyclopropylmethylcarbamate 2.80405.35 A383

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4-methyl-1,4-diazepane-1-carboxylate 2.08 448.34 A384

(S)-3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- acetamidopyrrolidine-1-carboxylate 2.48 462.32 A385

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 2- methoxyethyl(methyl)carbamate2.67 423.31 A386

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4-(2- methoxyethyl)piperazine-1-carboxylate 2.09 478.32 A387

(S)-3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 3- hydroxypyrrolidine-1-carboxylate 2.45 421.31 A388

(R)-2-((3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyloxy)carbonylamino) propanoic acid2.40 423.31 A389

3-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyl 4- isopropylpiperazine-1-carboxylate 2.08 462.36 A390

(S)-3-methyl-2-((3-(1-methyl- 4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)benzyloxy)carbonylamino) butanoic acid2.71 451.32

Examples A391N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N,N′-dimethyl-urea

Example A392 Ethylmethyl((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)carbamate

A391.1:N-Methyl-N-((6-(1-methyl-4-(methylamino)-1,6-dihydroimidaza[4,5-d]pyrrolo[2,3-b]pyridine-7-yl)pyridine-2-yl)methyl)-1H-imidazole-1-carboxamide

A solution of A247 (10.0 mg, 0.031 mmol), 1,1′-carbonyldiimidazole(40.21 mg, 0.248 mmol), and triethylamine (21.6 μL, 0.16 mmol) in DMF(1.0 mL) was heated at 80° C. for 30 min. After cooling to roomtemperature, DMF was removed. Water (1.0 mL) and 1:1 THF:EtOAc (2.0 mL)were added, The organic layer was washed with water, brine, dried(Na₂SO₄), and evaporated under vacuum to yield 9.0 mg M49.1 as a tansolid. HPLC (C): 100.0%, ret. time 1.79 min., MS (D): (M+H)⁺=416.41;(M−H)=414.41. The acyl imidazole was dissolved in dimethylamine (1.5 mLof a 2.0 M solution in MeOH) and heated at 80° C. for 15 min. The crudeproduct was purified by reverse-phase preparative HPLC to yield A391.1as an orange solid. HPLC (C): 99.14%, ret. time 2.28 min., LC/MS(M+H)⁺=380.26.

A391.2:N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N,N′-dimethyl-ureaand Ethylmethyl((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)carbamate

A somewhat cloudy solution of A391.1 (23.5 mg, 0.057 mmol) inmethylamine (1.5 mL of a 33% b/w solution in EtOH) was heated at 80° C.for 20 min. After solvent removal, the crude product was combined withcrude A392 from a previous reaction and purified by reversed-phasepreparative HPLC. Yield: A391 (10.0 mg, yellow solid, 26% assuming 1.0TFA salt) and A392 (7.5 mg, orange solid, 13% assuming 1.0 TFA salt).HPLC (C): A391, ret. time 1.84 min., LC/MS (M+H)⁺=379.30. HPLC (C):A392, ret. time 2.48 min., LC/MS (M+H)⁺=394.23

Examples A393 2-(dimethylamino)ethylmethyl((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)carbamateand isopropylmethyl((6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)carbamate

In a procedure similar to A391, A391.1 was reacted withN,N-dimethylethanolamine in isopropanol and purified by reverse phasechromatography. HPLC (C): A393 (tan-orange solid), ret. time 1.84 min.,LC/MS (M+H)⁺=437.33. HPLC (C): A394 (orange solid), ret. time 2.66 min.,LC/MS (M+H)⁺=409.34.

Example A395N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N-methyl-benzenesulfonamide

A suspension of A247 (10.0 mg, 0.031 mmol) and benzenesulfonyl chloride(4.77 μL, 0.037 mmol) in pyridine (1.5 mL) was stirred at 80° C. for 2h. Pyridine was removed under vacuum. MeOH was added (3.0 mL), theprecipitate was collected by filtration, rinsed with MeOH, and driedunder vacuum to yield A395 (7.0 mg, 49%, white solid). HPLC (C): 100%,ret. time 2.66 min., LC/MS (M+H)⁺=462.24.

Example A396N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N-methyl-methanesulfonamide

In a manner similar to A394, A247 was reacted withmethanesulfonylchloride to yield A396. HPLC (C): 100%, ret. time 2.10min., LC/MS (M+H)⁺=400.28.

Example A397N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2-methoxy-N-prop-2-enyl-acetamide

A397.1:N-[[6-[1,6-dihydro-1-methyl-4-(N-methyl-tert-butyloxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2-methoxy-N-prop-2-enyl-acetamide

NaH (0.10 g of a 60% mineral oil dispersion, 2.54 mmol) was added to asolution of 1G (0.38 g, 0.845 mmol) in DMF (4.0 mL). After 10 min.,allyl bromide was added (36.6 μL, 0.42 mmol) and the reaction mixturewas stirred for 30 min. More allyl bromide was added (36.6 μL, 0.42mmol) and stirring was continued for 2 h. After quenching with saturatedaq NH₄Cl solution (1.0 mL), DMF was removed under vacuum and the crudeproduct was purified by reverse-phase preparative HPLC to yield A397.1(0.30 g) as a tan-orange oil (83:17 A397.1: 1G by HPLC analysis). HPLC(C): 92.0%, ret. time 2.72 min., LC/MS (M+H)⁺=490.31.

A397.2:N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N-prop-2-enyl-amine

In a procedure similar to A247, A397.1 was treated with acid. The crudeproduct was neutralized with saturated aqueous NaHCO₃ solution, and thereaction mixture was evaporated to dryness under vacuum. The free basewas then dissolved in MeOH and the inorganic material was removed byfiltration. Yield after evaporation of MeOH under vacuum: 0.2525 g ofA397.2 as a tan solid (>100%). HPLC (C): 78.5%, ret. time 2.12 min.,LC/MS (M+H)⁺=348.31.

A397.3:N-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-2-methoxy-N-prop-2-enyl-acetamide

In a procedure similar to A248, A397.2 was reacted with methoxyaceticacid to yield A397. HPLC (C): 92.0%, ret. time 2.31 min., LC/MS(M+H)⁺=420.33.

Examples A398-A413

Examples A398-A413 were prepared from A247 in a similar fashion to A248.

For examples A398 and A399, the carboxylate salts A398.1 and A399.1 wereprepared as follows:

A398.1: (R)-(+)-2,2-dimethyl-1,3dioxalan-4-carboxylic acid, potassiumsalt

A solution of KOH (0.35 g, 6.24 mmol) in MeOH (7.24 mL) was addeddropwise to a solution of commercially available(R)-(+)-2,2-dimethyl-1,3 dioxalan-4-carboxylic acid, methyl ester (1.0g, 6.24 mmol) in MeOH (10.9 mL). The reaction mixture was stirred for 16h. More KOH was added (0.07 g in 27 μL of MeOH) and after 2 h thereaction mixture was evaporated to dryness. Ether was added (15.0 mL),and after a 30 sec. sonication, the precipitate was collected byfiltration, rinsed with ether, and dried under vacuum to yield A398.1(1.03 g, 90%) as a white solid. HPLC (C): 100%, ret. time 0.645 min.,LC/MS (M+H+ Na)⁺=169.11.

A399.1: (S)-(−)-2,2-dimethyl-1,3 dioxalan-4-carboxylic acid, potassiumsalt

A399.1 was prepared in a similar fashion to A398.1. HPLC (C): 100%, ret.time 0.645 min., LC/MS (M+H+ Na)⁺=169.11. TABLE A14

HPLC Retention MS Ex. R Name (min) Reported A398

(R)-N,2,2-trimethyl-N-((6-(1- methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridine-2-yl)methyl)-1,3- dioxolane-4-carboxamide 2.33 450.31 A399

(S)-N,2,2-trimethyl-N-((6-(1- methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridine-2-yl)methyl)-1,3- dioxolane-4-carboxamide 2.34 450.31 A400

(R)-2,3-dihydroxy-N-methyl- N-((6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridine-2-yl)methyl)propanamide 1.81 410.31 A401

(S)-2,3-dihydroxy-N-methyl- N-((6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridine-2-yl)methyl)propanamide 1.81 410.31 A402

N-methyl-N-((6-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)-2-(methylsulfonamido)acetamide 1.93 457.23 A403

3-(dimethylamino)-N-methyl- N-((6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)propanamide 1.75 421.36 A404

N-methyl-N-((6-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)-1H-imidazole-5-carboxamide 1.71 416.29 A405

N-methyl-N-((6-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)-4-sulfamoylbutanamide 1.91 471.31 A406

N-methyl-N-((6-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)-3-(piperidin-1-yl)propanamide 1.86 461.43 A407

N-methyl-N-((6-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2- yl)methyl)isonicotinamide 1.84427.38 A408

N,5-dimethyl-N-((6-(1- methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2- yl)methyl)pyrazine-2-carboxamide 2.24 442.30 A409

2-hydroxy-N-methyl-N-((6- (1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)propanamide 2.01 408.38 A410

N-methyl-N-((6-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)-2-(methylamino)acetamide 1.66 393.39 A411

(R)-N-methyl-N-((6-(1- methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2- yl)methyl)pyrrolidine-2-carboxamide 1.74 419.32 A412

(S)-N-methyl-N-((6-(1- methyl-4-(methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2- yl)methyl)pyrrolidine-2-carboxamide 1.74 419.31 A413

N-methyl-N-((6-(1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)-3-morpholinopropanamide 1.75 463.40

Example A4147-(6-chloropyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-c]pyrrolo[2,3-b]pyridine-4-amine

A414.1:Tert-butyl-6-amino-7-(6-chloropyridin-2-yl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-yl(methyl)carbamate

A1.12 (150 mg, 37 mmol), palladiumdichlorobistriphenylphosphine (22 mg,0.032 mmol), Copper iodide (7 mg, 0.032 mmol) and triethylamine (0.5 ml,3.7 mmol) in 5 ml DMF was degassed with nitrogen for fifteen minutes.The stirred reaction mixture was heated to 80° C.2-chloro-6-ethynylpyridine (51 mg, 0.367 mmol) was quickly added and thereaction mixture heated at 80° C. for 1 hour. The reaction mixture wascooled to room temperature concentrated in vacuo. The crude productmixture taken up in dichloromethane and filtered. The filtrate wasconcentrated in vacuo and the crude product chromatographed on SilicaGel (230-400 Mesh) eluting with 2% MeOH/98% CH₂Cl₂ to yield A414.1 (55mg, 50% yield). M+H+=413.18, 415.18. ¹H NMR (400 MHz) MeOD δ 7.82 (s,1H), 7.69 (m, 1H), 7.53 (d, 1H), 7.32 (d, 1H), 4.03 (s, 3H), 3.20 (s,3H), 1.31 (s, 9H)

Alternate Preparation of A414.1

A solution of A1.12 (1.0 g, 2.48 mmol) and 2-chloro-6-ethynylpyridine(0.68 g, 4.96 mmol) DMF (6.80 mL) was degassed by bubbling nitrogenthrough the solution. Dichlorobis(triphenylphosphine)Palladium II (0.104g, 0.148 mmol) and Copper(I) iodide (28.2 mg, 0.148 mmol) were added,and the reaction mixture was heated at 60° C. for 2 h. Additional2-chloro-6-ethynylpyridine was added (0.17 g, 1.24 mmol) and stirring at70° C. was continued for 3.0 h. DMF was removed under vacuum. The crudeproduct was partitioned between EtOAc (45.0 mL) and water; afterseparation, the EtOAc layer was washed with water, brine, dried(Na₂SO₄), and concentrated under vacuum. Flash chromatography of theresidue on silica gel, eluting with an EtOAc:hexane gradient followed byan EtOAc:MeOH gradient yielded 0.56 g of A414.1 pale tan solid (55%).HPLC (C): 80.5%, ret. Time 2.91 min., LC/MS (M+H)⁺=413.29.

A414.2:7-(6-chloropyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-c]pyrrolo[2,3-b]pyridine-4-amine

A414.1 (35 mg, 0.085 mmol), was dissolved in DMA (5 mL) and the solutionheated to 70° C. One equivalent of 1.0M potassium t-butoxide in THF (0.1ml, 0.09 mmol) was quickly added and the reaction heated at 70° C. forthirty minutes. A second equivalent of 1.0M potassium t-butoxide in THF(0.1 ml, 0.09 mmol) was quickly added and the reaction mixture stirredan additional thirty minutes. The reaction mixture was concentrated invacuo. The crude product residue was chromatographed on Silica Gel(230-400 Mesh) eluting with 2-5% MeOH/CH₂Cl₂ to give the Boc-protectedintermediate,tert-butyl-7-(6-chloropyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamateas an off-white solid. (20 mg, 57% yield). The solid was dissolved inmethylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL) was addedand the reaction mixture stirred for 0.25 h. The solvent was evaporatedunder reduced pressure to provide A414 (12 mg, 57%). M+H+=313.18,315.18. ¹H NMR (400 MHz) MEOD δ 8.02 (s, 1H), 7.75 (m, 2H), 7.41 (s,1H), 7.20 (d, 1H), 4.05 (s, 3 h), 3.15 (s, 3H).

Alternate Preparation of A414

Potassium tert-butoxide (0.94 mL of a 1.0M solution in THF, 0.94 mmol)in DMA (4.5 mL) was added to a solution of A414.1 (0.30 g, 0.73 mmol) inDMA (4.5 mL) under Ar and the reaction mixture was immediately placed ina pre-heated 80° C. oil bath. Stirring was carried out for 17.0 min. Thereaction mixture was evaporated to dryness under vacuum. Brine was added(10.0 mL), and after 2.0 min. of sonication, the precipitate wascollected by filtration, rinsed with water, and dried under vacuum toyield 0.2775 g oftert-butyl-7-(6-chloropyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamateas a light tan powder. Flash chromatography on silica gel, eluting withan EtOAc:MeOH gradient, yielded 0.2315 g of a light tan solid (77.0%).HPLC (C): 91.7%, ret. Time 2.92 min., LC/MS (M+H)⁺=413.29. The Bocprotected intermediatetert-butyl-7-(6-chloropyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamate,(940 mg, 22 mmol) was dissolved in 4N HCl in dioxane (10 mL) theresulting suspension was stirred for 15 minutes and the solventevaporated under reduced pressure. The product was evaporated frommethanol and then diethylether, and dried under vacuum to yield A414 asa tan powder (˜100%). M+H⁺=313.26, 315.27.

Example A4151,6-dihydro-7-[6-[(2-methoxyethyl)amino]-2-pyridinyl]-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A414 (15 mg, 0.048 mmol), 2-methoxyethylamine (1 ml, 11.5 mmol),2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorineon polystyrene [BEMP] (1 g, 2.2 mmol) in NMP was heated at 175° C. forfour hours. The reaction mixture was filtered. The filtrate wasconcentrated in vacuo. The crude product was purified using ReversePhase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm to give theproduct as an off-white solid. (10 mg, 60% yield). M+H 352.36. ¹H NMR(400 MHz) MEOD). δ 8.08 (s, 1H), 7.75 (m, 1H), 7.39 (m, 1H), 7.20 (d,1H), 6.70 (d, 1H). 4.10 (s, 3H), 3.66 (s, 3H), 3.65 (d, 2H), 3.41 (d,2H), 3.17 (s, 3H).

Example A416(2S)-3-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]amino]-1,2-propanediol

A solution of A414 (15.0 mg, 0.043 mmol) and1,8-Diazabicyclo[5.4.0]undec-7-ene (96.4 μL, 0.86 mmol) in(S)-(−)-3-Amino-1,2-propanediol (0.60 mL) was heated at 175° C. in asealed tube for 20.0 hrs. The reaction mixture was concentrated in a100° C. oil bath with a stream of nitrogen. Reverse-phase preparativeHPLC purification yielded 14.7 mg of A416 as a tan solid (71% assuming a1.0 TFA salt). HPLC (C): 96.5%, ret. Time 1.53 min., LC/MS(M+H)⁺=368.36.

Examples A417-A435

Examples A417-A435 were prepared in a fashion similar to that for A416.TABLE A15 HPLC Retention MS Ex. R Name (min) Reported A417

2-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]amino]-ethanol 1.67 338.33A418

N-[2-[[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]amino]ethyl]- acetamide 1.71379.37 A419

1,6-dihydro-7-[6-[(3- methoxypropyl)amino]-2- pyridinyl]-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 1.13 366.38 A420

1,6-dihydro-N,1-dimethyl-7- [6-(4-morpholinyl)-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 2.47 364.38A421

1,6-dihydro-N,1-dimethyl-7- [6-(1-pyrrolidinyl)-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 1.91 348.35A422

4-[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-1- piperazineethanol 1.87407.41 A423

1-[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-3-pyrrolidinol 1.64 364.38A424

1,6-dihydro-7-[6-[[2-(1H- imidazol-4-yl)ethyl]amino]-2-pyridinyl]-N,1-dimethyl- imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine1.62 388.35 A425

1,6-dihydro-N,1-dimethyl-7- [6-[[2-(4- morpholinyl)ethyl]amino]-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 1.73 407.40A426

1,6-dihydro-N,1-dimethyl-7- [6-[(2-phenylethyl)amino]-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 1.31 398.36A427

N-[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-N,N′,N′-trimethyl-1,2-ethanediamine 2.14 379.37 A428

1,6-dihydro-N,1-dimethyl-7- [6-[(phenylmethyl)amino]-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 2.39 384.34A429

1,6-dihydro-N,1-dimethyl-7- [6-[(3- pyridinylmethyl)amino]-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 1.67 385.37A430

N′-[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-N,N-dimethyl-1,2-ethanediamine 1.67 365.41 A431

7-[6-[(3- ethoxypropyl)amino]-2- pyridinyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 2.16 380.40 A432

1,6-dihydro-N,1-dimethyl-7- [6-[[2-(1- pyrrolidinyl)ethyl]amino]-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 1.73 391.38A433

1,6-dihydro-N,1-dimethyl-7- [6-(4-methyl-1-piperazinyl)-2-pyridinyl]-imidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 1.87 377.34A434

4-[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-1- piperazineacetic acid,ethyl ester 2.06 449.31 A435

1-acetyl-4-[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-piperazine ND 405.20

Example A436N-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]-acetamide

A436.1: N-(6-ethynylpyrdin-2-yl)acetamide

Anhydrous potassium carbonate (110 mg, 0.8 mmoles) was added to asolution of N-(6-((trimethylsilyl)ethynyl)pyridine-2-yl)acetamide (1.86g, 8 mmol) in 20 ml anhydrous methanol. The reaction mixture was stirredat room temperature for fifteen minutes then filtered. The filtrate wasconcentrated in vacuo. The crude product mixture was chromatographed onSilica Gel (230-400 Mesh) eluting with 2.5% MeOH/98% CH₂Cl₂ to yieldA436.1 as an off-white solid. (770 mg, 60% yield). M+H+=218.20 ¹H NMR(400 MHz) MEOD δ 8.13 (m, 1H), 7.75 (m, 1H), 7.27 (m, 1H), 3.65 (s, 1H),2.18 (s, 3H).

A436.2:tert-Butyl-6-amino-7-(6-acetamidopyridin-2-yl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-yl(methyl)carbamate

A1.12 (200 mg, 0.63 mmol), palladiumdichlorobistriphenylphosphine (44mg, 0.06 mmol), Copper iodide (12 mg, 0.06 mmol) and dsiisopropylamine(15 ml, 9.45 mmol) in 5 ml DMF was degassed with nitrogen for fifteenminutes. The stirred reaction mixture was heated to 80° C. A436.1 (100mg, 0.63 mmol) was quickly added and the reaction mixture heated at 80°C. for 1 hour. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The crude product mixture taken up indichloromethane and filtered. The filtrate was concentrated in vacuo andthe crude product mixture chromatographed on Silica Gel (230-400 Mesh)eluting with 2.5% MeOH/97.5% CH₂Cl₂ to yield A436.2 (135 mg, 50% yield).M+H+=436.31 ¹H NMR (400 MHz) MEOD δ 8.02 (s, 1H), 7.50 (s, 1H), 7.35((d, 1H), 6.95 (d, 1H), 4.33 (s, 3H), 3.44 (s, 3H), 3.30 ((s, 3H), 1.55(s, 9H).

A436.3:N-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]-acetamide

A436.2 (55 mg, 0.13 mmol), was dissolved in DMA (5 mL) and the solutionheated to 70° C. One equivalent of 1.0M potassium t-butoxide in THF(0.14 ml, 0.14 mmol) was quickly added and the reaction heated at 70° C.for thirty minutes. A second equivalent of 1.0M potassium t-butoxide inTHF (0.14 ml, 0.14 mmol) was quickly added and the reaction mixturestirred an additional thirty minutes. The reaction mixture wasconcentrated in vacuo. The crude product residue was chromatographed onSilica Gel (230-400 Mesh) eluting with 2-5% MeOH/CH₂Cl₂ to give theBoc-protected intermediate,tert-butyl-7-(6-acetamidopyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamateas an off-white solid. (26 mg, 60% yield). The solid was dissolved inmethylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL) was addedand the reaction mixture stirred for 0.25 h. The solvent was evaporatedunder reduced pressure to provide A436 (20 mg, 60%). M+H+=336.34 ¹H NMR(400 MHz) MEOD δ 9.20 (s, 1H), 8.02 (m, 1H), 7.78 (m, 1H), 7.71 (d, 1H),7.56 (s, 1H), 4.33 (s, 3H), 3.45 (s, 3H), 2.19 (s, 3H).

Example A4376-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinemethanol

A437.1:2-((tetrahydro-2H-pyran-2yloxy)methyl)-6-((trimethylsilyl)ethynyl)pyridine

2-Bromo-6-(tetrahydro-2H-pyran-2yloxy)methyl)pyridine (952 mg, 3.5mmol), palladiumdichlorobistriphenylphosphine (120 mg, 0.17 mmol),Copper iodide (33 mg, 0.17 mmol) and diisopropylamine (5 ml, 35 mmol) in5 ml DMF was degassed with nitrogen for fifteen minutes. The stirredreaction mixture was heated to 80° C. Trimethylsilylacetylene (1.5 ml,14 mmol) was quickly added and the reaction mixture heated at 80° C. for1 hour. The reaction mixture was cooled to room temperature concentratedin vacuo. The crude product mixture taken up in dichloromethane andfiltered. The filtrate was concentrated in vacuo and the crude productpurified by flash Silica Gel (230-400 Mesh) column chromatographyeluting with 1% MeOH/98% CH₂Cl₂ to yield A437.1 (758 mg, 75% yield).M+H+=290.31 ¹H NMR (400 MHz) MEOD δ 7.51 (m, 1H), 7.33 (m, 1H), 7.19 (m,1H), 4.68 (m, 3H), 3.66 (m, 1H), 3.25 (m, 1H), 1.48 (m, 6H), 0.08 (s,9H).

A437.2: 2-ethynyl-6-(tetrahydro-2H-pyran-2yloxy)methyl)pyridine

Anhydrous potassium carbonate (36 mg, 0.26 mmoles) was added to asolution of A437.1 (752 mg, 2.6 mmol) in 10 ml anhydrous methanol. Thereaction mixture was stirred at room temperature for fifteen minutesthen filtered. The filtrate was concentrated in vacuo. The crude productmixture was chromatographed on Silica Gel (230-400 Mesh) eluting with2.5% MeOH/98% CH₂Cl₂ to yield A437.2 as an off-white solid. (406 mg, 65%yield). M+H+=218.20 ¹H NMR (400 MHz) MeOD δ 7.87 (m, 1H), 7.58 (m, 1H),7.50 (m, 1H), 4.61 (d, 1H), 3.92 (m, 3H), 3.58 (m, 2H), 1.93 (m, 6H).

A437.3:Tert-butyl-6-amino-1-methyl-7-(6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)ethynyl)-1H-imidazo[4,5-c]pyridine-4-yl(methyl)carbamate

A1.12 (2.01 g, 5 mmol), palladiumdichlorobistriphenylphosphine (175 mg,0.25 mmol), Copper iodide (48 mg, 0.25 mmol) and dsiisopropylamine (21ml, 150 mmol) in 21 ml DMF was degassed with nitrogen for fifteenminutes. The stirred reaction mixture was heated to 80° C. A437.2 (3.26g, 15 mmol) was quickly added and the reaction mixture heated at 80° C.for 1 hour. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The crude product mixture taken up indichloromethane and filtered. The filtrate was concentrated in vacuo andthe crude product mixture chromatographed on Silica Gel (230-400 Mesh)eluting with 2.5% MeOH/97.5% CH₂Cl₂. (2.3 g, 88% yield). M+H+=493.21 ¹HNMR (400 MHz) MeOD δ 7.96 (s, 1H) 7.92 (m, 1H), 7.59 (m, 2H), 4.86 (dd,2H), 4.18 (s, 3H), 3.93 (t, 1H), 3.52 (m, 2H), 3.50 (s, 3H), 1.64 (m,6H), 1.43 (s, 9H).

A437.4:6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinemethanol

A437.3 (2.6 g, 5 mmol), was dissolved in DMA (5 mL) and the solutionheated to 70° C. One equivalent of 1.0M potassium t-butoxide in THF (5.5ml, 5.5 mmol) was quickly added and the reaction heated at 70° C. forthirty minutes. A second equivalent of 1.0M potassium t-butoxide in THF(5.5 ml, 5.5 mmol) was quickly added and the reaction mixture stirred anadditional thirty minutes. The reaction mixture was concentrated invacuo. The crude product residue was chromatographed on Silica Gel(230-400 Mesh) eluting with 2-5% MeOH/CH₂Cl₂ to give the Boc-protectedintermediate,tert-butylmethyl(1-methyl-7-(6-(tetrahydro-2H-pyran-2-yloxy)methyl)pyridine-2-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]carbamateas an off-white solid. (1.8 g, 88% yield). The solid was dissolved inTHF (30 mL) and 6N HCl (30 mL) was added and the reaction mixture heatedat 50° C. for one h. The solvent was evaporated under reduced pressureto provide the product as a HCl salt. (1.28 g, 80%). The HCl salt wasstirred with 50 ml sat'd Na₂CO₃ solution and 100 ml dichloromethane. Thedichloromethane extract was separated, dried (Na₂SO₄) and concentratedin vacuo to give the product A437 (0.90 g, 80%). M+H+=309.32 ¹H NMR (400MHz) MeOD δ 8.54 (s, 1H), 8.34 (m, 1H), 8.17 (d, 1H), 7.89 (s, 1H), 7.72(d, 1H), 4.91 (s, 2H), 4.16 (s, 1H), 3.18 (s, 1H).

Example A4386-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinemethanol,methylcarbamate (ester)

Methylisocyanate (50 mg, 0.88 mmol) was added to a stirred mixture ofA437 (50 mg, 0.16 mmol), triethylamine (1 ml) in tetrahydrofuran (5 ml)at room temperature. After complete addition the reaction mixture wasstirred at room temperature for sixteen hours. The reaction mixture wasconcentrated in vacuo. The crude product residue was washed with diethylether to give the product as a tan solid. A438 (45 mg, 76% yield). M+H366.36 ¹H NMR (400 MHz) MeOD δ 7.95 (s, 1H), 7.68 (m, 2H), 7.30 (s, 1H),7.10 (d, 1H), 5.06 (s, 2H), 3.99 (s, 3H), 3.18 (s, 3H), 2.61 (s, 3H).

Example A439(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methylethylcarbamate

Ethylisocyanate (17 mg, 0.24 mmol) was added to a stirred mixture ofA437 (31 mg, 0.10 mmol), triethylamine (1 ml) in tetrahydrofuran (5 ml)at room temperature. After complete addition the reaction mixture wasstirred at room temperature for sixteen hours. The reaction mixture wasconcentrated in vacuo. The crude product residue was chromatographedusing Reverse Phase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm togive the product as a tan solid. A439 (20 mg, 50% yield). M+H 380.33 ¹HNMR (400 MHz) MEOD δ 8.11 (s, 1H), 7.85 (m, 2H), 7.47 (s, 1H), 7.32 (d,1H), 5.24 (s, 2H), 4.20 (s, 3H), 3.33 (s, 3H), 3.14 (m, 2H), 1.35 (t,3H).

Example A440(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl1-(2,2,2-trifluoroacetyl)piperidin-4-ylcarbamate

2,2,2-trifluoro-1-(4-isocyanatopiperidin-1-yl)ethanone (40 mg, 0.18mmol) was added to a stirred mixture of A437 (50 mg, 0.166 mmol),triethylamine (1 ml) in tetrahydrofuran (5 ml) at room temperature.After complete addition the reaction mixture was stirred at roomtemperature for sixteen hours. The reaction mixture was concentrated invacuo. The crude product residue was chromatographed using ReversePhase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm to give theproduct as a tan solid. A440 (23 mg, 27% yield). M+H 531.27.

Example A441(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl4-(2-methoxyethyl)piperazine-1-carboxylate

A441.1:(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl1H-imidazole-1-carboxylate

1,1-carbonyl diimidazole (81 mg, 0.50 mmol) was added in portions to astirred mixture of A437 (103 mg, 0.38 mmol) in chloroform (20 ml) heatedat 60° C. After complete addition the reaction mixture was heated at 60°C. for one hour. The reaction mixture was cooled to room temperature andwashed with 3×25 ml water. The chloroform extract was separated, dried(Na₂SO₄), and concentrated in vacuo to give the product as an off-whitesolid. A441.1 (100 mg, 76% yield). M+H 403.23. ¹H NMR (400 MHz) MEOD δ8.02 (s, 1H), 7.76 (m, 3H), 7.36 (m, 2H), 7.20 (m, 1H), 5.20 (s, 2H),4.0 (s, 3H), 3.15 (s, 3H).

A441.2:(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl4-(2-methoxyethyl)piperazine-1-carboxylate

A mixture of 1-(2-methoxyethyl)piperazine (29 mg, 0.20 mmol), A441.1 (40mg, 0.10 mmol), triethylamine (0.5 ml) in chloroform (20 ml) was stirredat room temperature for sixteen hours. The reaction mixture wasconcentrated in vacuo. The crude product residue was chromatographedusing Reverse Phase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm togive the product as a tan solid. A441 (25 mg, 52% yield). M+H 479.35. ¹HNMR (400 MHz) CDCl3, δ 8.73 (d, 1H), 8.03 (s, 1H), 8.01 (d, 1H), 7.60(s, 1H), 7.34 (d, 1H), 5.46 (s, 2H), 4.13 (s, 3H), 3.57 (d, 2H), 3.37(m, 13H).

Example A442(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl2-(dimethylamino)ethyl(methyl)carbamate

A mixture of N,N,N-trimethylethylenediamine (21 mg, 0.20 mmol), A441.1(40 mg, 0.10 mmol), triethylamine (0.5 ml) in chloroform (20 ml) wasstirred at room temperature for sixteen hours. The reaction mixture wasconcentrated in vacuo. The crude product residue was purified usingReverse Phase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm to giveA442 as a tan solid (15 mg, 34% yield). M+H 437.39. ¹H NMR (400 MHz)MEOD δ 8.13 (s, 1H), 7.87 (m, 2H), 7.44 (s, 1H), 7.30 (m, 1H), 5.32 (s,2H), 4.15 (s, 3H), 3.80 (m, 4H), 3.40 (m, 3H), 3.32 (s, 3H), 3.00 (s,3H), 2.88 (s, 3H).

Example A443(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl4-fluorobenzylcarbamate

A mixture of 4-fluorobenzylamine (25 mg, 0.20 mmol), A441.1 (40 mg, 0.10mmol), triethylamine (0.5 ml) in chloroform (20 ml) was stirred at roomtemperature for sixteen hours. The reaction mixture was concentrated invacuo. The crude product residue was purified using ReversePhase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm to yield A443 asa tan solid (20 mg, 44% yield). M+H 460.33. ¹H NMR (400 MHz) MEOD δ8.129 s, 1H), 7.84 (d, 2H), 7.48 (s, 1H), 7.36 (m, 3H), 7.04 (m, 2H),5.27 (s, 2H), 4.34 (s, 2H), 4.16 (s, 3H), 3.26 (s, 3H)

Example A444(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl2-acetamidoethylcarbamate

A mixture of N-(aminoethyl)acetamide (21 mg, 0.20 mmol), A441.1 (40 mg,0.10 mmol), triethylamine (0.5 ml) in chloroform (20 ml) was stirred atroom temperature for sixteen hours. The reaction mixture wasconcentrated in vacuo. The crude product residue was chromatographedusing Reverse Phase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm togive the product as a tan solid. A444 (12 mg, 27% yield). M+H 437.33. ¹HNMR (400 MHz) MEOD δ 8.09 (s, 1H), 7.90 (m, 2H), 7.36 (s, 1H), 7.30 (d,1H), 5.28 (d, 2H), 4.12 (s, 3H), 3.33 (m, 4H), 3.19 (s, 3H), 1.97 (s,3H).

Example A445(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl2-(methylamino)ethylcarbamate

A mixture of N-methylethylenediamine (15 mg, 0.20 mmol), A441.1 (40 mg,0.10 mmol), triethylamine (0.5 ml) in chloroform (20 ml) was stirred atroom temperature for sixteen hours. The reaction mixture wasconcentrated in vacuo. The crude product residue was purified usingReverse Phase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm to yieldA445 as a tan solid. (15 mg, 37% yield). M+H 409.35. ¹H NMR (400 MHz)MEOD δ 8.13 (s, 1H), 7.84 (m, 2H), 7.43 (s, 1H), 7.34 (m, 1H), 5.29 (s,2H), 4.15 (s, 2H), 3.55 (m, 4H), 3.19 (s, 3H), 2.75 (s, 3H).

Example A446(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl4-methylpiperazine-1-carboxylate

A mixture of 1-methylpiperazine (20 mg, 0.20 mmol), A441.1 (40 mg, 0.10mmol), triethylamine (0.5 ml) in chloroform (20 ml) was stirred at roomtemperature for sixteen hours. The reaction mixture was concentrated invacuo. The crude product residue was chromatographed using ReversePhase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm to give theproduct as a tan solid. A446 (14 mg, 33% yield). M+H 435.35. ¹H NMR (400MHz) MEOD δ 8.16 (s, 1H), 7.89 (m, 2H), 7.51 (s, 1H), 7.35 (m, 1H), 5.33(s, 2H), 4.18 (s, 3H), 3.32 (m, 11H), 2.96 (s, 3H).

Example A447ethyl(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methylcarbonate

Ethylchloroformate (20 mg, 0.18 mmol) was slowly added to a stirredsolution of A437 (50 mg, 0.16 mmol), triethylamine (0.5 ml) intetrahydrofuran cooled to 0° C. After complete adition the reaction wasallowed to warm to room temperature then stirred for four hours. Thereaction mixture was quenched with one ml. of 10% HCl(aq) solution andextracted with ethyl acetate (3/20 ml). The ethyl acetate extracts werecombined, dried (Na₂SO₄) and concentrated in vacuo. The crude productresidue was chromatographed using Reverse Phase-PreparativeHPLC/Phenomenex LUNA 5μ, 100×21.2 mm to give the product as a tan solid.A447 (25 mg, 65% yield). M+H 381.30. ¹H NMR (400 MHz) MEOD δ 8.04 (s,1H), 7.78 (m, 2H), 7.36 (s, 1H), 7.25 (m, 1H), 5.23 (s, 2H), 4.23 (m,2H), 4.08 (s, 3H), 3.19 (s, 3H), 1.30 (m, 3H).

Example A4486-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl-2-methoxyacetate

2-methoxyacetylchloride (20 mg, 0.18 mmol) was slowly added to a stirredsolution of A437 (50 mg, 0.16 mmol), triethylamine (0.5 ml) intetrahydrofuran cooled to 0° C. After complete adition the reaction wasallowed to warm to room temperature then stirred for four hours. Thereaction mixture was quenched with one ml. of 10% HCl(aq) solution andextracted with ethyl acetate (3/20 ml). The ethyl acetate extracts werecombined, dried (Na₂SO₄) and concentrated in vacuo. The crude productresidue was purified using Reverse Phase-Preparative HPLC/PhenomenexLUNA 5μ, 100×21.2 mm to give A448 as a tan solid. (25 mg, 65% yield).M+H 381.30. ¹H NMR (400 MHz) MeOD δ 8.02 (s, 1H), 7.96 (m, 1H), 7.40 (d,1H), 7.70 (s, 1H), 5.40 (s, 2H), 4.34 (s, 2H), 4.25 (s, 3H), 3.52 (s,3H), 3.26 (s, 3H).

Example A4491,6-dihydro-7-[6-[[(3-methoxypropyl)amino]methyl]-2-pyridinyl]-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A solution of A216 (62 mg, 16 mmol) in THF was cooled to 0° C. A 1.0Msolution of lithium aluminium hydride (0.2 ml, 0.20 mmol) was slowlyadded to the cooled solution. After complete addition the reactionmixture was stirred at room temperature two hours then heated at refluxfor two hours. The reaction mixture was carefully quenched with 0.2 mlH₂O, followed by the addition of 0.2 ml 15% NaOH, then followed by theaddition of 0.6 ml H₂O. The organic layer was separated and concentratedin vacuo. The crude product residue was purified using ReversePhase-Preparative HPLC/Phenomenex LUNA 5μ, 100×21.2 mm to provide A449as a tan solid. (20 mg, 30% yield). M+H 381.30. ¹H NMR (400 MHz) MEOD δ8.12 (s, 1H), 7.90 (m, 2H), 7.52 (s, 1H), 7.30 (m, 1H), 4.50 (s, 2H),4.18 (s, 3H), 3.74 (m, 2H), 3.579 m, 2H), 3.33 (s, 3H), 3.36 (s, 3H),1.89 m, 2H).

Example A450N-[2-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]ethyl]-acetamide

A450.2: N-(2-(6-(trimethylsilyl)ethynyl)pyridine-2-yl)acetamide

A450.1 (840 mg, 3.5 mmol), palladiumdichlorobistriphenylphosphine (120mg, 0.17 mmol), Copper iodide (33 mg, 0.177 mmol) and diisopropylamine(5 ml, 35 mmol) in 5 ml DMF was degassed with nitrogen for fifteenminutes. The stirred reaction mixture was heated to 80° C.Trimethylsilylacetylene. (1.5 ml, 14 mmol) was quickly added and thereaction mixture heated at 80° C. for 1 hour. The reaction mixture wascooled to room temperature concentrated in vacuo. The crude productmixture taken up in dichloromethane and filtered. The filtrate wasconcentrated in vacuo and the crude product purified by Silica Gelchromatography (230-400 Mesh) eluting with 1% MeOH/98% CH₂Cl₂ to yieldA450.2 (682 mg, 75% yield) M+H+=261.28 ¹H NMR (400 MHz) MEOD δ 8.08 (m,1H), 7.59 (m, 2H), 3.65 (m, 2H), 3.21 (m, 2H), 1.88 (s, 3H), 0.23 (s,9H).

A450.3: N-(2-(6-ethynylpyridin-2-yl)ethyl)acetamide

Anhydrous potassium carbonate (36 mg, 0.26 mmoles) was added to asolution of A450.2 (682 mg, 2.6 mmol) in 10 ml anhydrous methanol. Thereaction mixture was stirred at room temperature for fifteen minutesthen filtered. The filtrate was concentrated in vacuo. The crude productmixture was purified by Silica Gel (230-400 Mesh) chromatography elutingwith 2.5% MeOH/98% CH₂Cl₂ to give A450.3 as an off-white solid. (220 mg,55% yield). M+H+=189.16 ¹H NMR (400 MHz) MEOD δ 8.15 (m, 1H), 7.58 (m,2H), 4.57 (s, 1H), 3.66 (m, 2H), 3.22 (m, 2H), 1.90 (s, 3H).

A450.4: tert-butyl7-((6-(2-acetamidoethyl)pyridin-2-yl)ethynyl)-6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

-   -   A1.12 (604 mg, 1.5 mmol), palladiumdichlorobistriphenylphosphine        (72 mg, 0.11 mmol), Copper iodide (21 mg, 0.11 mmol) and        diisopropylamine (0.5 ml, 3.7 mmol) in 5 ml DMF was degassed by        bubbling nitrogen through the mixture for thirty minutes. The        stirred reaction mixture was heated to 80° C. A450.3 (353 mg,        1.88 mmol) was quickly added and the reaction mixture heated at        80° C. for 1 hour. The reaction mixture was cooled to room        temperature and concentrated in vacuo. The crude product mixture        taken up in dichloromethane and filtered. The filtrate was        concentrated in vacuo and the crude product mixture        chromatographed on Silica Gel (230-400 Mesh) eluting with 2%        MeOH/98% CH₂Cl₂ to give A450.4 (247 mg, 53% yield). M+H+=464.30.

A450.5:N-[2-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]ethyl]-acetamide

A450.4 (147 mg, 0.30 mmol), was dissolved in DMA (5 mL) and the solutionheated to 77° C. One equivalent of 1.0M potassium t-butoxide in THF (0.3ml, 0.30 mmol) was quickly added and the reaction heated at 70° C. forthirty minutes. A second equivalent of 1.0M potassium t-butoxide in THF(0.3 ml, 0.30 mmol) was quickly added and the reaction mixture stirredan additional thirty minutes. The reaction mixture was concentrated invacuo. The crude product residue was purified by Silica Gel (230-400Mesh) chromatography eluting with 2-5% MeOH/CH₂Cl₂ to give theBoc-protected intermediate,tert-butyl-7-(6-(2-acetamidoethyl)pyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-yl(methyl)carbamateas an off-white solid. (76 mg, 52% yield). The solid was dissolved inmethylene chloride (0.5 mL) and trifluoroacetic acid (0.5 mL) was addedand the reaction mixture stirred for 0.25 h. The solvent was evaporatedunder reduced pressure to provide A450 (37 mg, 63%). M+H+=364.26. 1H NMP(400 MHz) MEOD δ 8.14 (s, 1H), 7.84 (m, 2H), 7.52 (s, 1H), 7.30 (m, 1H),4.18 (s, 3H), 3.77 (m, 2H), 3.29 (s, 3H), 3.11 (m, 2H), 1.94 (s, 3H).

Example A4517-(6-(2-aminomethyl)pyridine-2-yl)-N-1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-amine

A450 (24 mg, 0.05 mmol), was dissolved in ethanol (5 mL) and 6N HCl (aq)solution and the solution was heated 80° C. for sixteen hours. Thereaction mixture was concentrated in vacuo to give the hydrochloridesalt as a yellow solid. The solid was stirred in a mixture of sat'dsodium carbonate(aq) solution and dichloromethane for 1 h. Thedichloromethane extract was separated, dried (Na2SO4), and concentratedin vacuo to provide A451 as a yellow solid. (16 mg, 96%). M+H+=322.31.¹H NMR (400 MHz) MeOD δ 7.45 (s, 1H), 7.20 (m, 2H), 6.90 (s, 1H), 6.55(m, 1H), 3.33 (s, 3H), 2.75 (m, 4H), 2.49 (s, 3H).

Example A452[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]methyl-carbamicacid methyl ester

A solution of A247 (10.0 mg, 0.031 mmol), 1,1′-carbonyldiimidazole(40.21 mg, 0.248 mmol), and triethylamine (21.6 μL, 0.16 mmol) in DMF(1.0 mL) was heated at 80° C. for 30 min. After cooling to roomtemperature, DMF was removed. Water (1.0 mL) and 1:1 THF:EtOAc (2.0 mL)were added, The organic layer was washed with water, brine, dried(Na₂SO₄), and evaporated under vacuum to yield 9.0 mg M49.1 as a tansolid. HPLC (C): 100.0%, ret. time 1.79 min., MS (D): (M+H)⁺=416.41;(M−H)=414.41. The acyl imidazole was dissolved in dimethylamine (1.5 mLof a 2.0 M solution in MeOH) and heated at 80° C. for 15 min. Thesolvent was evaporated under reduced pressure and the crude product waspurified by reversed-phase preparative HPLC to yield A452 an orangesolid. HPLC (C): 99.14%, ret. time 2.28 min., LC/MS (M+H)⁺=380.26.

Example A453N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-methanesulfonamide

Methanesulfonyl chloride (18.3 mg, 0.16 mmol) was added in one portionto A3 (50 mg, 0.12 mmol) and triethylamine (18.7 mg, 0.19 mmol) in THF(2 mL) at 0 C under a nitrogen atmosphere. The mixture was allowed towarm to room temperature over 3 hrs, before quenching with water (1 mL)and extracting with ethyl acetate (2×10 mL). The combined organics weredried (MgSO₄), evaporated in vacuo and the residue treated with 4N HClin dioxane (2 mL). After stirring at room temperature for 2 hrs, themixture was evaporated in vacuo. The residue suspended in hot methanol(1 mL) before filtering to yield A453 (10 mg) as a white solid. HPLC YMCS-5 4.6×33 mm (2 min grad): retention time 1.33 min, M+H+=385.38. ¹H NMR(400 MHz, DMSO) δ 11.93 (s, 1H), 7.70 (br. s, 1H), 7.63 (d, J=7.7 Hz,1H), 7.47 (t, J=6.2 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.14-7.12 (m, 2H),4.09 (d, J=6.1 Hz, 1H), 4.03 (s, 3H), 2.96 (s, 3H), 2.78 (s, 3H).

Example A454N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]phenyl]methyl]-N-(2-methoxyethyl)-methanesulfonamide

TMAD (9 mg, 0.052 mmol) was added in one portion to A453 (25 mg, 0.052mmol), 2-methoxyethanol (4 mg, 0.052 mmol) and tributylphosphine (11 mg,0.052 mmol) in anhydrous DMF (0.2 mL). The reaction mixture was heatedto 140° C. for 10 min in the microwave before cooling to roomtemperature, evaporating in vacuo and purifying by preparative HPLC toyield A454 (1 mg). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time1.64 min, M+H+=443.34.

Example A4551,6-dihydro-N-(2-methoxyethyl)-1-methyl-4-(methylamino)-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide

EDC (8.2 mg, 0.065 mmol) was added in one portion to a mixture of theacid A168.1 (10 mg, 0.029 mmol), HOBt (4 mg, 0.05 mmol) and DIPEA (0.06mL) in anhydrous acetonitrile (0.5 mL) and the resulting mixture wasallowed to stir at room temperature for 30 min before addition of2-methoxyethylamine (4 mg, 0.05 mmol). The mixture was heated overnightto 80° C. in a screw-capped vial before cooling to room temperature,evaporating in vacuo and treating with 4N HCl in dioxane (2 mL). Aftercontinued stirring for 2 hr, the mixture was purified by preparativeHPLC to yield A455 (5.6 mg, 98%) HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 0.98 min, M+H⁺=303.30.

Example A4564-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]carbonyl]-morpholine

A456.1: 6-Trimethylsilanylethynyl-pyridine-2-carboxylic acid ethyl ester

TMS-Acetylene (1.36 mL, 9.61 mmol) was added dropwise to thecommercially available 2-bromo-5-carboxypyridine ethyl ester (2.0 g,8.73 mmol), CuI (83 mg, 0.44 mmol) and palladiumdichlorobistriphenylphosphine (400 mg, 0.58 mmol) in triethylamine (30mL) at room temperature under a nitrogen atmosphere. The reactionmixture was stirred at room temperature for 1 hr before evaporating invacuo. Diethyl ether (50 mL) was added to the residue and the slurryfiltered. The filtrate was evaporated in vacuo to yield the crudeproduct A456.1 which (2.68 g) which was used immediately without furtherpurification.

A456.2: 6-Ethynyl-pyridine-2-carboxylic acid methyl ester

Potassium hydroxide solution (1 pellet dissolved in 1 mL of water) wasadded in one portion to A456.1 (2.68 g) in anhydrous methanol (30 mL).After stirring at room temperature for 1 hr, the reaction was evaporatedin vacuo and diethyl ether (50 mL) added to the residue. The slurry wasfiltered to yield A446.2 (1.38 g) as a brown powder which was usedimmediately without further purification. HPLC YMC S-5 4.6×33 mm (2 mingrad): retention time 0.93 min, M+H⁺=162.12

A456.3:6-[6-Amino-4-(tert-butoxycarbonyl-methyl-amino)-1-methyl-1H-imidazo[4,5-c]pyridin-7-ylethynyl]-pyridine-2-carboxylicacid methyl ester

A1.12 (2.0 g, 4.96 mmol), dichlorobis(triphenylphosphine)palladium (232mg, 0.33 mmol), A456.2 (2.91 g, 19.85 mmol) and triethylamine (18 mL)were each added to N,N-dimethylformamide (20 mL) and nitrogen bubbledthrough the resulting mixture for 5 min. The reaction mixture was heatedat 90° C. for 1 hr under a nitrogen atmosphere before cooling to roomtemperature and evaporating the solvent in vacuo. Water (50 mL) wasadded to the residue and the mixture sonicated for 10 min beforefiltering. The solid (6 g) was purified by column using 10% MeOH indichloromethane as eluent to provide 2.55 g (100%) of A456.3 as a darksolid. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.53 min,M+H⁺=437.33

A456.4:6-[4-(tert-Butoxycarbonyl-methyl-amino)-1-methyl-6-(2,2,2-trifluoro-acetylamino)-1H-imidazo[4,5-c]pyridin-7-ylethynyl]-pyridine-2-carboxylicacid methyl ester

Trifluoroacetic anhydride (1.63 mL, 11.70 mmol) was added dropwise over5 min to a cooled (0° C.) solution of A456.3 (2.55 g, 5.85 mmol) andtriethylamine (2.5 mL, 17.55 mmol) in THF (50 mL) under a nitrogenatmosphere. The cooling bath was removed after 10 min and the reactionmixture allowed to stir at room temperature for 1 hr before evaporatingin vacuo. The residue was taken up in dichloromethane (50 mL) and washedwith saturated sodium bicarbonate solution (25 mL). The organic layerwas separated and dried (MgSO₄), then evaporated in vacuo to yield thecrude product A456.4 which was used immediately without furtherpurification (2.78 g). HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 1.67 min, M+H⁺=533.27

A456.5:6-[1,6-dihydro-1-methyl-4-(N-methyl-tertbutoxycarbonylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinecarboxylicacid

Potassium carbonate (250 mg, 1.79 mmol) anddichlorobistriphenylphosphine (68 mg, 0.097 mmol) were each added in oneportion to a solution of A456.4 (0.86 g, 1.62 mmol) in dimethylacetamide(20 mL). at room temperature under a nitrogen atmosphere. The reactionwas heated to 130° C. for 1 hr before cooling to room temperature andevaporating in vacuo. The residue was partitioned between water (30 mL)and ethyl acetate (50 mL). The separated organic layer was dried(MgSO4), evaporated in vacuo and purified by column chromatography using5% MeOH in ethyl acetate to yield azaindole ester (258 mg). The aqueouslayer was purified by preparative hplc to yield the desired carboxylicacid A456.5 (220 mg). HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 1.44 min, M+H⁺=423.31. ¹H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 8.51(s, 1H), 8.37-8.35 (m, 1H), 8.16-8.11 (m, 1H), 8.01-7.98 (m, 1H), 7.82(s, 1H), 4.19 (s, 3H), 3.36 (s, 3H), 1.34 (s, 9H).

A456.6:4-[[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]carbonyl]-morpholine

BOP-Cl (11 mg, 0.44 mmol) was added in one portion to a mixture ofA456.5 (20 mg, 0.048 mmol), morpholine (5 mg, 0.0521 mmol) and DIPEA(0.06 mL) in anhydrous DMF (0.5 mL) and the resulting mixture wasallowed to stir at room temperature for 30 min in a screw-capped vialbefore evaporating in vacuo and treating with 4N HCl in dioxane (2 mL).After continued stirring for 2 hr, the mixture was purified bypreparative HPLC to yield A456 (10 mg, 98%) HPLC YMC S-5 4.6×33 mm (2min grad): retention time 1.78 min, M+H⁺=392.18

Examples A457

The compounds in Table 16 were prepared in a similar manner to A456starting with A456.5 and using the appropriate amine. TABLE A16 HPLCRetention MS Ex. R Name (min) Reported A457

1-[[6-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrro1o[2,3-b]pyridin-7-yl]- 2-pyridinyl]carbonyl]-4- piperidinol 1.62406.19 A458

(2R)-1-[[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrro1o[2,3-b]pyridin-7-yl]- 2-pyridinyl]carbonyl]-2-(methoxymethyl)pyrrolidine 1.53 420.40 A459

(3R)-1-[[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]carbonyl]-3- pyrrolidinol1.28 392.35 A460

N-cyclopropyl-6-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinecarboxamide 1.82 362.34

Example A461N-[1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]ethyl]-acetamide

A461.1: (Z)-1-(6-Bromopyridin-2-yl)ethanone oxime

A mixture of 2-acetyl-6-bromopyridine (commercially available) (1.00 g,5.00 mmol) and hydroxylamine hydrochloride (0.694 g, 10.0 mmol) inpyridine (6 mL) was stirred at room temperature overnight. The solventwas removed under reduced pressure, and the residue was diluted withdichloromethane, washed with water, and dried over anhydrous sodiumsulfate. Concentration under reduced pressure afforded a quantitativeyield of A461.1 as a white solid. The compound had an HPLC retentiontime=1.95 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; SolventA=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1%TFA) and a LC/MS M⁺¹=215 and 217.05.

Alternate Preparation of A461.1

A mixture of 2-acetyl-6-bromopyridine (10.0 g, 0.050 mol) andhydroxylamine hydrochloride (6.90 g, 0.10 mol) in pyridine (50 mL) wasstirred at room temperature overnight. The solvent was removed underreduced pressure, and the residue was diluted with ethyl acetate (200mL), washed with water (100 mL), and dried over anhydrous sodiumsulfate. Concentration under reduced pressure afforded a 10.75 g ofA461.1 as an off-white solid.

A461.2: 1-(6-Bromopyridin-2-yl)ethanamine

To a solution of A461.1 (1.08 g, 5.00 mmol) in trifluoroacetic acid (8mL) was added zinc dust (1.96 g, 30.0 mmol) slowly in small portions.After the addition was complete, the reaction mixture was stirred for 30min. The mixture was carefully poured into a solution of 2M aqueoussodium hydroxide (68 mL) and dichloromethane (34 mL) cooled with an icebath. The resulting mixture was filtered under reduced pressure, and theorganic layer was collected, washed with water, and dried over anhydroussodium sulfate. Concentration under reduced pressure afforded 0.738 g,74%) of A461.2 as a yellow oil. The compound had an HPLC retentiontime=0.667 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; SolventA=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1%TFA) and a LC/MS M⁺¹=201.09 and 203.09.

Alternate Preparation of A461.2

To a stirring suspension of A461.1 (10.75 g, 0.050 mol) in acetic acid(200 mL) and water (100 mL) was slowly added zinc dust (11.0 g, 0.170mol) in portions over 1 hr. The reaction mixture was filtered throughCelite and concentrated under reduced pressure. The residue wasneutralized with a 25% aqueous solution of ammonium hydroxide andextracted with dichloromethane (3×100 mL). The organic layers werecombined, washed with brine, and dried over anhydrous sodium sulfate.Concentration under reduced pressure afforded 9.90 g (98%) of A461.2 asbrownish oil.

A461.3: N-(1-(6-Bromopyridin-2-yl)ethyl)acetamide

A mixture of A461.2 (0.738 g, 3.67 mmol), acetic anhydride (0.74 mL),and pyridine (0.74 mL) was stirred at room temperature for 3 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was diluted with dichloromethane, washed with water, wash with asaturated aqueous solution of sodium bicarbonate, and dried overanhydrous sodium sulfate. Concentration under reduced pressure followedby purification by flash silica gel chromatography using mixture ofmethanol in dichloromethane (1%-2.5%-5%) to give A461.3 (0.474 g, 53%)as a viscous yellow oil. The compound had an HPLC retention time 1.29min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH,90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and aLC/MS M⁺¹=243 and 245.04.

Alternate Preparation of A461.3

A mixture of A461.2 (9.90 g, 0.050 mol), acetic anhydride (6 mL), andpyridine (10 mL) in anhydrous tetrahydrofuran (50 mL) was stirred atroom temperature overnight. The reaction mixture was diluted with ethylacetate (200 mL), washed with water (100 mL), and dried over anhydroussodium sulfate. Concentration under reduced pressure afforded A461.3(12.03 g, 98%) as a viscous yellow oil.

A461.4: N-(1-(6-((Trimethylsilyl)ethynyl)pyridin-2-yl)ethyl)acetamide

A mixture of A461.3 (0.474 g, 1.95 mmol), dichlorobis(triphenylphospine)palladium II (0.082 g, 0.117 mmol), and copper iodide (0.019 g, 0.098mmol) in anhydrous dimethylformamide (8 mL) was degassed well undernitrogen. To the mixture was added the acetylene (0.413 mL, 2.92 mmol)and triethylamine (1.36 mL, 9.75 mmol), and the reaction mixture wasstirred at room temperature for 10 min. and then heated at 75° C. for 3hr. The reaction mixture was filtered through a pad of Celite toppedwith a pad of silica gel, and the pad was rinsed with dichloromethane.Concentration under reduced pressure followed by purification by flashsilica gel chromatography using a 5% mixture of methanol indichloromethane afforded 0.365 g (70%) of A461.4 as a light brownviscous oil. The product had an HPLC retention time=2.69 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=261.28.

Alternate Preparation of A461.4

To a mixture of A461.3 (10.0 g, 0.041 mol),dichlorobis(triphenylphospine) palladium II (1.43 g, 2.00 mmol), copperiodide (0.390 g, 2.00 mmol), and diisopropylamine (57 mL, 0.41 mol) inanhydrous dimethylformamide (57 mL) degassed well under nitrogen at 77°C. was added trimethylacetylene (7.0 mL, 0.062 mol). The reactionmixture was stirred at 77° C. for 1 hr, cooled to room temperature, andfiltered. Concentration under reduced pressure followed by purificationby flash silica gel chromatography using a mixture of methanol indichloromethane (0%-1%) provided 6.66 g (96%) of A461.4 as a orangeviscous oil.

A461.5 N-(1-(6-Ethynylpyridin-2-yl)ethyl)acetamide

A mixture of A461.4 (0.356 g, 1.37 mmol) and potassium carbonate (0.020g, 0.144 mmol) in methanol (3 mL) was stirred at room temperature for 80min. The reaction mixture was concentrated under reduced pressure, andthe residue was purified by flash silica gel chromatography using amixture of methanol in dichloromethane (1%-5%) to give 0.167 g (64%) ofA461.5 as a yellowish-orange solid. The compound had an HPLC retentiontime=0.807 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; SolventA=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1%TFA) and a LC/MS M⁺¹=189.18.

Alternate Preparation of A461.5

A mixture of A461.4 (6.66 g, 0.026 mol) and potassium carbonate (0.350g, 2.60 mmol) in anhydrous methanol (52 mL) was stirred at roomtemperature for 15 min. The reaction mixture was filtered andconcentrated under reduced pressure, and the residue was purified byflash silica gel chromatography using a mixture of methanol indichloromethane (0%-2%) to give 3.70 g (70%) of A461.5 as a viscousorange oil.

A461.6: Tert-butyl7-((6-(1-acetamidoethyl)pyridin-2-yl)ethynyl)-6-amino-1-methyl-1H-imidazo-[4,5-c]pyridin-4-yl(methyl)carbamate

A mixture of A461.5 (0.167 g, 0.887 mmol), A1.12 (0.311 g, 0.771 mmol),dichlorobis(triphenyl-phosphine)palladium II (0.032 g, 0.046 mmol),copper (I) iodide (0.007 g, 0.039 mmol), and triethylamine (0.540 mL,3.86 mmol) in anhydrous dimethylformamide (3 mL) was degassed well withnitrogen. The reaction mixture was immersed in an oil bath at 80° C. andstirred for 45 min. The solvent was removed under reduced pressure, andthe residue was purified by flash silica gel chromatography using amixture of methanol in dichloromethane (1%-10%) to give 0.271 g (76%) ofA461.6 as a light orange solid. The compound had an HPLC retentiontime=2.27 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; SolventA=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1%TFA) and a LC/MS M⁺¹=464.34.

Alternate Preparation fo A461.6

A mixture of A1.12 (4.03 g, 0.010 mol), dichlorobis(triphenylphosphine)palladium II (0.35 g, 5.00 mmol), copper (I) iodide (0.095 g, 5.00mmol), and diisopropylamine (21 mL, 0.150 mmol) in anhydrousdimethylformamide (21 mL) was degassed well with nitrogen and heated at77° C. Acetylene A461.5 (2.82 mL, 0.015 mol) in 5 mL of anhydrousdimethylformamide was added, and the reaction mixture was stirred at 77°C. for 60 min. The solvent was removed under reduced pressure, and theresidue was purified by flash silica gel chromatography using a mixtureof methanol in dichloromethane (0%-2.5%) to give 5.42 g of crude productas a brown solid. The compound was dissolved in 10 mL of dichloromethaneand then pipetted into 100 mL of diethyl ether with stirring. Thesuspension was filtered and dried well to give 4.50 g (97%) of A461.6 asa tan solid.

A461.7: Tert-butyl7-(6-(1-acetamidoethyl)pyridin-2-yl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo-[2,3-b]pyridin-4-yl(methyl)carbamate

To a solution of A461.6 (2.09 g, 0.451 mmol) in anhydrousdimethylacetamide (2.5 mL) under nitrogen was added a 1.0 M solution ofpotassium tert-butoxide in tetrahydrofuran (0.50 mL, 0.496 mmol), andthe reaction mixture was heated for 20 min. A second 0.50 mL was added,and the reaction mixture was stirred for an additional 10 min. Thesolvent was removed under reduced pressure, and the residue was purifiedby flash silica gel chromatography using a 5% mixture of methanol indichloromethane to give 0.125 g (60%) of A461.7 as a yellow solid. Thecompound had an HPLC retention time=2.41 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA;Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=464.34.

Alternate Preparation of A461.7

A solution of A61.6 (4.00 g, 9.00 mmol) in anhydrous dimethylacetamide(20 mL) was stirred under a stream of nitrogen for 20 min. The reactionmixture was immersed into an oil bath at 80° C. and stirred for 5 min. A1.0 M solution of potassium tert-butoxide in tetrahydrofuran (10.0 mL,10.0 mmol) was added, and the reaction mixture was heated for 15 min. Asecond addition of potassium tert-butoxide (1M solution in THF, 10.0 mL)was added, and the reaction mixture was stirred for an additional 15min, cooled to room temperature, and quenched with a saturated aqueoussolution of sodium bicarbonate (50 mL). The aqueous mixture wasextracted with dichloromethane (3×100 mL), and the organic layers werecombined and concentrated under reduced pressure. Purification by flashsilica gel chromatography using a mixture of methanol in dichloromethane(1%-2.5%) provided 3.60 g (85%) of A461.7 as a yellow solid.

A461.8:N-[1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]ethyl]-acetamide

A solution of A461.7 (0.123 g, 0.265 mmol) in trifluoroacetic acid (4.5mL) was stirred at room temperature for 30 min. The trifluoroacetic acidwas removed under reduced pressure, and the residue was diluted withdichloromethane, washed with a saturated aqueous solution of sodiumbicarbonate, and dried over anhydrous sodium sulfate. Concentrationunder reduced pressure provided 0.90 g (94%) of A461 as a yellow solid.The compound had an HPLC retention time=2.01 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA;Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MS M⁺¹=364.31. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J=6.60 Hz, 3H) 1.94 (s, 3H) 2.99(d, J=4.40 Hz, 3H) 4.03 (s, 3H) 5.01-5.07 (m, 1H) 6.67 (d, J=4.40 Hz,1H) 7.05 (d, J=7.15 Hz, 1H) 7.33 (d, J=2.20 Hz, 1H) 7.66-7.72 (m, 2H)7.90 (s, 1H) 8.53 (d, J=8.80 Hz, 1H) 11.75 (s, 1H)

Example A462 and Example A463

A461 (50 mg) was separated using a ChiralPAK AD 250×4.6 mm 10 microncolumn (CO₂/IPA with 0.1% Diethylamine—70/30 at 100 Bar; 35° C.; 2mL/min.) Enantiomer A (fast eluting) A462 had a chiral HPLC retentiontime=7.02 min. (99.687% ee). Enantiomer B (slow eluting) A463 chiralHPLC retention time=9.56 min. (99.655% ee)—[Column: ChiralPAK AD 250×4.6mm 10 micron (CO₂/IPA with 0.1% Diethylamine—70/30 at 100 Bar; 35° C.; 2mL/min.)].

Example A4647-[6-(1-aminoethyl)-2-pyridinyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A homogeneous solution of A461 (0.012 g 0.033 mmol) in concentratedhydrochloric acid (1.5 mL) was heated in the microwave at 150° C. for 30min. The hydrochloric acid was removed under reduced pressure, and theresidue was diluted with dichloromethane, neutralized with a saturatedaqueous solution of sodium bicarbonate, and dried over anhydrous sodiumsulfate. Concentration under reduced pressure followed by purificationby silica gel chromatography using a mixture of 10% methanol indichloromethane (+05% NH₄OH) afforded 10.0 mg (91%) of A464 as a yellowsolid. The compound had an HPLC retention time=1.95 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1% TFA) and a LC/MSM⁺¹=322.30. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.46 (d, J=6.60 Hz, 3H) 1.79(brs, 2H) 3.19 (d, J=4.95 Hz, 3H) 4.03 (s, 3H) 4.10 (d, J=6.60 Hz, 1H)5.54 (d, J=4.95 Hz, 1H) 7.00 (s, 1H) 7.02 (d, J=7.70 Hz, 1H) 7.50 (d,J=7.70 Hz, 1H) 7.56-7.60 (m, 2H) 9.87 (s, 1H)

Example A465N-[1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]ethyl]-2-methoxy-acetamidechiral, absolute stereochemistry unassigned

A465.1:7-[6-(1-aminoethyl)-2-pyridinyl]-1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A solution of Enantiomer A463 (0.021 g, 0.058 mmol), absolute ethanol(2.5 mL) and concentrated hydrochloric acid (2.5 mL) was heated at 55°C. overnight. By HPLC and LC/MS, starting material was still present.The residue was concentrated under reduced pressure and re-subjected tothe reaction conditions. The reaction mixture was stirred at 55° C. for2.5 days, at which point, it was complete. Concentration under reducedpressure provided a quantitative yield of the bishydrochloride saltA465.1 as a light orange solid. The compound had an HPLC retentiontime=1.48 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; SolventA=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10% H₂O, and 0.1%TFA) and a LC/MS M⁺¹=322.31.

A465.2:N-[1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]ethyl]-2-methoxy-acetamide

To a mixture of A465.1 (0.023 g, 0.58 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.012 g,0.087 mmol), 1-hydroxybenzotriazole (0.017 g, 0.087 mmol), anddiisopropylethylamine (0.060 mL, 0.347 mmol) in anhydrousdimethylformamide (2.5 mL) was added methoxyacetic acid (0.0066 mL,0.087 mmol). The homogeneous reaction mixture was heated at 75° C. for 1hr. The solvent was removed under reduced pressure, and the residue wasdiluted with dichloromethane, washed with a saturated aqueous solutionof sodium bicarbonate, and dried over anhydrous sodium sulfate.Concentration under pressure followed by purification by flash silicagel chromatography using a 5% mixture of methanol in dichloromethaneafforded 0.019 g (83%) of A465 as a light tan solid. The compound had anHPLC retention time=2.08 min. (Column: Chromolith SpeedROD 4.6×50 mm—4min.; Solvent A=10% MeOH, 90% H₂O, and 0.1% TFA; Solvent B=90% MeOH, 10%H₂O, and 0.1% TFA) and a LC/MS M⁺¹=394.36, ¹H NMR (500 MHz, d⁶-DMSO) δppm 1.42 (d, J=6.60 Hz, 3H) 2.98 (d, J=4.40 Hz, 3H) 3.34 (s, 3H)3.86-3.94 (m, 2H) 4.02 (s, 3H) 5.05-5.11 (m, 1H) 6.69 (d, J=4.40 Hz, 1H)7.07 (d, J=7.15 Hz, 1H) 7.31 (s, 1H) 7.67-7.74 (m, 2H) 7.90 (s, 1H) 8.47(d, J=8.25 Hz, 1H) 11.79 (s, 1H)

Example A466N-[1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]propyl]-acetamide

A446.1: 6-Bromo-pyridine-2-carboxylic acid tert-butylamide

2,6-Dibromopyridine (40 g, 170 mmol) in THF (200 mL) was added dropwiseover 1 hr to a cooled (−78 C) solution of n-butyllithium (2.0M inpentane, 85 mL, 170 mmol) in THF (100 mL) under a nitrogen atmosphere.The mixture was allowed to stir for an additional 15 min, thentert-butyl isocyanate was added dropwise over 5 min. The resultingreaction mixture was allowed to warm slowly to room temperatureovernight before quenching with saturated ammonium chloride solution(200 mL) and extracting with ethyl acetate (2×100 mL). The combinedorganics were dried (MgSO₄) and evaporated in vacuo to yield the cudeproduct A466.1 (42.4 g) as a dark brown oil which was used immediatelywithout further purification. HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.76 min, M+H⁺=203.08

A466.2: 6-Bromo-pyridine-2-carbonitrile

Thionyl chloride (10 mL, 138 mmol) was added in one portion to the amideA466.1 (1.07 g, 4.18 mmol) at room temperature under a nitrogenatmosphere. The resulting mixture was heated to 85° C. for 1 hr beforecooling to room temperature and evaporating in vacuo. The residue wasbasified to pH14 using sodium hydroxide solution (5M, 20 mL). Thisaqueous phase was then extracted with ethyl acetate (2×25 mL), thecombined organics dried (MgSO₄), evaporated in vacuo and the residuepurified by column chromatography using ethyl acetate as eluent to yieldA466.2 (0.5 g) as a beige solid. HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.02 min, M+H⁺=185.06

A466.3: 1-(6-Bromo-pyridin-2-yl)-propylamine

Ethyl magnesium bromide (3.0 mL, 3.0 mmol) was added dropwise over 10min to a solution of the pyridine nitrile A466.2 (500 mg, 2.75 mmol) inTHF (5 mL) at room temperature under a nitrogen atmosphere. Afterstrring for 30 min at room temperature, the reaction mixture was thencooled to 0° C. and anhydrous methanol added (2.75 mL) followed bysodium borohydride (15 mg, 3.0 mmol). The mixture was allowed to warm toroom temperature over 1 hr before quenching with saturated ammoniumchloride solution (10 mL) and stirring overnight at room temperature.The mixture was diluted with water (20 mL) and extracted with ethylacetate (3×30 mL). The combined organics were dried (MgSO4), evaporatedin vacuo and purified by column chromatography using 10% MeOH in ethylacetate as eluant to yield A466.3 (237 mg). HPLC YMC S-5 4.6×33 mm (2min grad): retention time 0.87 min, M+H⁺=217.15

A466.4: N-[1-(6-Bromo-pyridin-2-yl)-propyl]-acetamide

Acetyl chloride (0.087 mL, 1.22 mmol) was added dropwise to a mixture ofthe amine A466.3 (237 mg, 1.11 mmol) and triethylamine (0.34 mL, 2.44mmol) in THF (3 mL) at 0 C under a nitrogen atmosphere. The cooling bathwas removed and the reaction allowed to warm to room temperature over 1hr. The reaction mixture was filtered to remove thetriethylamine-hydrochloride salt and the filtrate was evaporated invacuo to yield the crude product A466.4 (299 mg) which was usedimmediately without further purification. HPLC YMC S-5 4.6×33 mm (2 mingrad): retention time 1.31 min, M+H⁺=259.16

A466.5: N-[1-(6-Trimethylsilanylethynyl-pyridin-2-yl)-propyl]-acetamide

TMS-Acetylene (0.21 mL, 1.46 mmol) was added dropwise to the pyridinebromide A466.4 (299 mg, 1.17 mmol), copper (I) iodide (11 mg, 0.06 mmol)and palladium dichlorobistriphenylphosphine (55 mg, 0.078 mmol) intriethylamine (5 mL) and DMF (1 mL) at room temperature under a nitrogenatmosphere. The reaction mixture was heated to 80° C. for 30 min beforecooling to room temperature and evaporating in vacuo. Diethyl ether wasadded (20 mL) and the salt filtered. The filtrate was evaporated invacuo and purified by column chromatography using 1:1 ethylacetate:hexane as eluent to yield A466.5 (250 mg). HPLC YMC S-5 4.6×33mm (2 min grad): retention time 1.84 min, M+H⁺=275.32

A466.6: N-[1-(6-Ethynyl-pyridin-2-yl)-propyl]-acetamide

Sodium hydroxide (2N, 0.5 mL) was added in one portion to theTMS-acetylene A466.5 (250 mg) in THF (3 mL) at room temperature. Afterstrring for 1 hr, the reaction mixture was diluted with water (5 mL) andextracted with ethyl acetate (2×15 mL). The combined organics were dried(MgSO4) and evaporated in vacuo to yield the crude product A466.6 (141mg, 77%) which was used immediately without further purification. HPLCYMC S-5 4.6×33 mm (2 min grad): retention time 0.95 min, M+H⁺=203.26

A466.7:{7-[6-(1-Acetylamino-propyl)-pyridin-2-ylethynyl]-6-amino-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl}-methyl-carbamicacid tert-butyl ester

A1.12 (225 mg, 0.56 mmol), dichlorobis(triphenylphosphine)palladium (26mg, 0.037 mmol), A466.6 (141 mg, 0.70 mmol) and triethylamine (2 mL)were each added to N,N-dimethylformamide (2 mL) and nitrogen bubbledthrough the resulting mixture for 5 min. The reaction mixture was heatedat 80° C. for 1 hr under a nitrogen atmosphere before cooling to roomtemperature and evaporating the solvent in vacuo. Diethyl ether wasadded to the residue (10 mL) and filtered. The filtrate was evaporatedin vacuo purified by silica gel column chromatography using 10% MeOH inethyl acetate as eluent to provide 172 mg of A466.7. HPLC YMC S-5 4.6×33mm (2 min grad): retention time 1.47 min, M+H⁺=478.36.

A466.8:N-[1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]propyl]-acetamide

Potassium tert-butoxide (1.0M in THF, 0.9 mL, 0.9 mmol) was addeddropwise over 2 min to a solution of A466.7 (172 mg, 0.36 mmol) in DMA(4 mL) at room temperature under a nitrogen atmosphere. The reaction washeated to 90° C. for 1 hr before cooling to room temperature andevaporating in vacuo. The residue was purified by column chromatographyusing 5% MeOH in ethyl acetate as eluent to yield A466.8 (91 mg). HPLCYMC S-5 4.6×33 mm (2 min grad): retention time 1.58 min, M+H⁺=478.36.

A466.9:N-[1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]propyl]-acetamide

Trifluoroacetic acid in dichloromethance (20% solution, 5 mL) was addedin one portion to A466.8 and the resulting reaction mixture was stirredat room temperatuire for 1 hr before evaporating in vacuo. The residuewas partitioned between ethyl acetate (5 mL) and saturated sodiumhydrogen carbonate solution (5 mL). The aqueous phase was extracted withethyl acetate (2×10 mL) and the combined organics were dried (MgSO₄) andevaporated in vacuo to yield A466 (39 mg) as a tan powder. HPLC YMC S-54.6×33 mm (2 min grad): retention time 1.47 min, M+H⁺=378.38

Examples A467 and A468

Separation of enantiomers was achieved using a chiracel AD column4.6×250 mm, 10 micron, Hex/MeOH/EtOH/DEA=75:12.5:12.5:0.1 to yieldenantiomer one at time t=9.26 min and enantiomer 2 at time t=11.36 min.

Example A469(gammaS)-gamma-amino-6-[1,6-dihydro-1-methyl-4-(methylamino)imidazol-[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinepropanoltrihydrochloride

A469.1:(S)-2-{[1-(6-Bromo-pyridin-2-yl)-meth-(E)-ylidene]-amino}-3-methyl-butyricacid methyl ester

Anhydrous magnesium sulfate (5.4 g), 6-bromopyridine-2-carboxaldehyde(5.0 g, 26.9 mmol) and triethylamine (3.75 mL, 26.9 mmol) were eachadded sequentially in one portion to a cooled (0° C.) solution of(L)-valine methyl ester hydrochloride (4.51 g, 26.9 mmol) and thereaction mixture was allowed to warm slowly to room temperatureovernight under a nitrogen atmosphere. The mixture was then filtered andthe filter cake washed with diethyl ether (100 mL) before evaporatingthe filtrate in vacuo. The residue was purified by column chromatographyusing 5:1 hexane/ethyl acetate as eluent to yield A469.1 (7.1 g, 88%).HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 0.86 min,M+H⁺=202.08

A469.2: (S)-2-[(S)-1-(6-Bromo-pyridin-2-yl)-allylamino]-3-methyl-butyricacid methyl ester

Dimethyl zinc (2.0M in toluene, 9.85 mL, 19.7 mmol) was added toanhydrous THF (10 mL) under a nitrogen atmosphere and the solutioncooled to −78° C. Vinylmagnesium bromide (1.0M in THF, 19.7 mL, 19.7mmol) was then added dropwise over 10 min and the solution allowed tostir at −78° C. under a nitrogen atmosphere for 30 min. A solution ofthe imine A469.1 (5.87 g, 19.7 mmol) in THF (10 mL) was then addeddropwise to the zincate solution at −78° C. over 1 hr. The resultingreaction mixture was then allowed to stir for an additional 1 hr at −78°C. before quenching with 10% sodium hydrogen carbonate solution (100 mL)and warming to room temperature. The mixture was diluted with water (50mL) and extracted with diethyl ether (2×200 mL), the combined organicphases were then dried (MgSO₄) and evaporated in vacuo to yield A469.2(6.35 g, 99%) which was used immediately without further purification.HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.21 min,M+H⁺=329.21

A469.3:(S)-2-[(S)-1-(6-Bromo-pyridin-2-yl)-allylamino]-3-methyl-butan-1-ol

Lithium aluminium hydride (2.0M in THF, 6.10 mL, 12.19 mmol) was addeddropwise over 30 min to a cooled (−5° C.) solution of the ester A469.2(3.98 g, 12.19 mmol) in THF (40 mL) under a nitrogen atmosphere. Thereaction mixture was allowed to stir for 1 hr before quenching at −5° C.with water (0.46 mL), 15% sodium hydroxide solution (0.46 mL) and water(1.4 mL) each added dropwise. The mixture was then allowed to warm toroom temperature before filtering and washing with diethyl ether (30mL). The filtrate was washed with water (30 mL) and the separatedorganic layer was dried (MgSO₄), evaporated in vacuo and purified bycolumn chromatography using 4:1 hexane:ethyl acetate as eluent to yieldA469.3 (2.68 g). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time1.13 min, M+H+=301.18

A469.4: (S)-1-(6-Bromo-pyridin-2-yl)-allylamine

40% Aqueous methylamine solution (8.25 mL) followed by periodic acid(5.63 g in 80 mL of water) were each added in one portion to a solutionof the alcohol A469.3 (2.04 g, 6.85 mmol) in methanol/THF (9:1 v/v, 80mL). The reaction mixture was stirred at room temperature for 3 hrsbefore adding water (90 mL). The methanol was removed in vacuo and theresidue extracted with diethyl ether (3×200 mL). The combined organiclayers were dried (MgSO₄) and evaporated in vacuo to yield A469.4 (1.72g) which was used immediately without further purification. HPLC YMC S-54.6×33 mm (2 min grad): retention time 0.76 min, M+H⁺=215.10

A469.5: [(S)-1-(6-Bromo-pyridin-2-yl)-allyl]-carbamic acid tert-butylester

Triethylamine (6.1 mL, 43.65 mmol) and BOC-anhydride (2.0 g, 9.17 mmol)were each added in one portion to a cooled (0° C.) solution of the amineA469.4 (1.72 g, 8.73 mmol) in anhydrous dichloromethane (100 mL) under anitrogen atmosphere. The reaction mixture was allowed to warm slowly toroom temperature overnight before quenching with saturated sodiumhydrogen carbonate solution (50 mL). The organic layer was dried (MgSO₄)and evaporated in vacuo to give a crude residue which was purified bycolumn chromatography using 10:1 hexane:ethyl acetate as eluent to yieldA469.5 (2.22 g, 86%). HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 2.01 min, M+H⁺ (−Boc)=215.10

A469.6: [(S)-1-(6-Bromo-pyridin-2-yl)-3-hydroxy-propyl]-carbamic acidtert-butyl ester

9-BBN (0.5M in THF, 6.75 mL) was added dropwise over 2 min to a solutionof A469.5 (1.0 g, 3.37 mmol) in THF (20 mL) at room temperature under anitrogen atmosphere. The reaction mixture was allowed to stir at roomtemperature for 2 hrs before cooling to 0° C. and adding hydrogenperoxide (30%, 1.69 mL) and sodium hydroxide (3M, 1.69 mL). The mixturewas then heated to 50° C. for 1 hr before cooling to room temperature.The aqueous layer was separated and extracted with diethyl ether (2×30mL), the combined organic layers dried (MgSO₄), evaporated in vacuo andpurified by column chromatography using 2:1 hexane/ethyl acetate aseluent to give A469.6 (818 mg, 63%). HPLC YMC S-5 4.6×33 mm (2 mingrad): retention time 1.51 min, M+Na⁺=355.19

A469.7:[(S)-1-(6-Bromo-pyridin-2-yl)-3-(tetrahydro-pyran-2-yloxy)-propyl]-carbamicacid tert-butyl ester

para-Toluenesulfonic acid monohydrate (116 mg, 0.61 mmol) was added inone portion to a solution of the alcohol A469.6 (802 mg, 2.43 mmol) anddihydropyran (0.23 mL, 2.55 mmol) in dichloromethane (10 mL) at 0 Cunder a nitrogen atmosphere. The cooling bath was removed and thereaction mixture allowed to warm to room temperature over 2 h beforequenching with saturated sodium hydrogen carbonate solution (10 mL). Theorganic layer was dried (MgSO₄) and evaporated in vacuo to yield A469.7(1.12 g) which was used immediately without further purification. HPLCYMC S-5 4.6×33 mm (2 min grad): retention time 1.88 min, M+Na⁺=439.19.

A469.8:[(S)-3-(Tetrahydro-pyran-2-yloxy)-1-(6-trimethylsilanylethynyl-pyridin-2-yl)-propyl]-carbamicacid tert-butyl ester

TMS-Acetylene (0.98 mL, 6.91 mmol) was added dropwise to the pyridinebromide A469.7 (2.29 g, 5.53 mmol), CuI (53 mg, 0.28 mmol) and palladiumdichlorobistriphenylphosphine (260 mg, 0.37 mmol) in triethylamine (30mL) at room temperature under a nitrogen atmosphere. The reactionmixture was heated to 80 C for 30 min before cooling to room temperatureand evaporating in vacuo. Diethyl ether was added (20 mL) and the saltfiltered. The filtrate was evaporated in vacuo yield A469.8 (2.50 g)which was used immediately without further purification. HPLC YMC S-54.6×33 mm (2 min grad): retention time 2.12 min, M+H⁺=433.32

A469.9:[(S)-1-(6-Ethynyl-pyridin-2-yl)-3-(tetrahydro-pyran-2-yloxy)-propyl]-carbamicacid tert-butyl ester

Sodium hydroxide (2N, 5.8 mL) was added in one portion to the A469.8(2.5 g, 5.79 mmol) in THF (50 mL) at room temperature. After stirringfor 1 hr, the reaction mixture was diluted with water (20 mL) andextracted with diethyl ether (2×30 mL). The combined organics were dried(MgSO4), evaporated in vacuo and purified by column chromatography using2:1 hexane/ethyl acetate as eluent to yield A469.9 (1.31 g). HPLC YMCS-5 4.6×33 mm (2 min grad): retention time 1.77 min, M+H⁺=361.34

A469.10:(6-Amino-7-{6-[(S)-1-tert-butoxycarbonylamino-3-(tetrahydro-pyran-2-yloxy)-propyl]-pyridin-2-ylethynyl}-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl)methyl-carbamicacid tert-butyl ester

A1.12 (484 mg, 1.2 mmol), dichlorobis(triphenylphosphine)palladium (56mg, 0.08 mmol), A469.9 (540 mg, 1.5 mmol) and triethylamine (4 mL) wereeach added to N,N-dimethylformamide (2 mL) and nitrogen bubbled throughthe resulting mixture for 5 min. The reaction mixture was heated at 75°C. for 3 hrs under a nitrogen atmosphere before cooling to roomtemperature and evaporating the solvent in vacuo. The residue waspurified by silica gel column chromatography using 2:1 ethylacetate/hexane as eluent to provide 449 mg (59%) of A469.10. HPLC YMCS-5 4.6×33 mm (2 min grad): retention time 1.81 min, M+H⁺=636.40

A469.11:[7-{6-[(S)-1-tert-Butoxycarbonylamino-3-(tetrahydro-pyran-2-yloxy)propyl]-pyridin-2-ylethynyl}-1-methyl-6-(2,2,2-trifluoro-acetylamino)-1H-imidazo[4,5-c]pyridin-4-yl]-methyl-carbamicacid tert-butyl ester

Trifluoroacetic anhydride (0.185 mL, 1.33 mmol) was added dropwise over5 min to a cooled (0 C) solution of A469.10 (423 mg, 0.67 mmol) andtriethylamine (0.28 mL, 2.00 mmol) in THF (10 mL) under a nitrogenatmosphere. The cooling bath was removed after 10 min and the reactionmixture allowed to stir at room temperature for 1 hr before evaporatingin vacuo. The residue was taken up in dichloromethane (50 mL) and washedwith saturated sodium bicarbonate solution (25 mL). The organic layerwas separated and dried (MgSO₄), then evaporated in vacuo to yield thecrude product A469.11 which was used immediately without furtherpurification (513 mg). HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 1.97 min, M+H⁺=732.34

A469.12:(S)-tert-butyloxycarbonylamino-6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridin-3-(tetrahydropyran-2-yl)propanol

Potassium carbonate (107 mg, 0.772 mmol) anddichlorobistriphenylphosphine palladium (II) (30 mg, 0.042 mmol) wereeach added in one portion to a solution of A469.11 (513 g, 0.7 mmol) indimethylacetamide (8 mL). at room temperature under a nitrogenatmosphere. The reaction was heated to 120° C. for 2 hrs beforeevaporating in vacuo and purifying by column chromatography using 2:1ethyl acetate:hexane to yield A469.12 (305 mg, 72% over two steps). HPLCYMC S-5 4.6×33 mm (2 min grad): retention time 1.87 min, M+H⁺=636.35

A469.13:(S)-amino-6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinepropanol

Concentrated hydrochloric acid (assuming 10M, 0.44 mL, 4.36 mmol) wasadded dropwise to a solution of A469.12 (277 mg, 0.436 mmol) in THF (10mL) and the reaction mixture stirred at room temperature for 3 hrsbefore evaporating in vacuo. Diethyl ether (20 mL) was added to theresidue and the solid filtered to yield A469 (194 mg, 88%). HPLC YMC S-54.6×33 mm (2 min grad): retention time 1.06 min, M+H⁺=352.29.

-   -   Column: Chiralpak AD 250×4.6 mm ID; 10 μm    -   Temperature: 35° C.    -   Mobil Phase: Hex/EtOH/DEA=20:80:0.1    -   Flow rate: 1.0 mL/min    -   Injection volume: 5˜15 μl    -   UV Detection: 368 nm        Retention time=12.3 min, 95.6% enantiomeric excess.

Example A470N-[(1S)-1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]-3-hydroxypropyl]-2-methoxy-acetamide

EDC (23 mg, 0.12 mmol) was added in one portion to a mixture ofmethoxyacetic acid (11 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA(0.041 mL) in anhydrous DMF (2 mL) and the resulting mixture was allowedto stir at room temperature for 30 min before addition of A469 (50 mg,0.109 mmol). The mixture was heated to 70° C. for 2 hrs in ascrew-capped vial before cooling to room temperature and evaporating invacuo. The residue was partitioned between ethyl acetate (5 mL) andwater (2 mL). The separated aqueous layer was adjusted to a pH of 7-8and extracted with ethyl acetate (3×30 mL). The combined organics weredried (MgSO₄), evaporated in vacuo and purified by column chromatography(5% MeOH in EtOAc) to yield A470 (29 mg). HPLC YMC S-5 4.6×33 mm (2 mingrad): retention time 1.13 min, M+H⁺=424.28

The compounds in Table A17 were prepared in a similar manner to A470 byreacting A469 and the appropriate carboxylic acid. TABLE A17

HPLC Retention MS Ex. R Name (min) Reported A471 CH₃—N-[(1S)-1-[6-[1,6-dihydro-1- 1.11 394.30 methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-3-hydroxypropyl]-acetamide A472

N-[(1S)-1-[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-3- hydroxypropyl]-3-methoxy-propanamide 1.14 438.29

Example A473(S)-7-(6-(1-amino-3-methoxypropyl)pyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A473.1: [(S)-1-(6-Ethynyl-pyridin-2-yl)-3-methoxy-propyl]-carbamic acidtert-butyl ester

Sodium hydride (60% dispersion in oil, 80 mg, 1.99 mmol) was added inone portion to a solution of the alcohol derived from A469.9 bytreatment with 1N HCl (440 mg, 1.59 mmol) in anhydrous THF (8 mL) cooledto 0° C. under a nitrogen atmosphere. The reaction mixture was stirredfor 10 min before the dropwise addition of methyl iodide (0.10 mL, 1.67mmol). The reaction mixture was allowed to warm slowly to roomtemperature overnight before quenching with water (5 mL) and extractingdiethyl ether (2×20 mL). The combined organics were dired (MgSO₄),evaporated in vacuo and purified by column chromatography using 3:1hexane:ethyl acetate to yield A473.1 (205 mg). HPLC YMC S-5 4.6×33 mm (2min grad): retention time 1.60 min, M+H⁺=291.27

A473.2:{6-Amino-7-[6-((S)-1-tert-butoxycarbonylamino-3-methoxy-propyl)pyridin-2-ylethynyl]-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl}-methyl-carbamicacid tert-butyl ester

A1.12 (239 mg, 0.593 mmol), dichlorobis(triphenylphosphine)palladium II(28 mg, 0.04 mmol), A473.1 (189 mg, 0.652 mmol) and diisopropylamine (2mL) were each added to N,N-dimethylformamide (1.7 mL) and nitrogenbubbled through the resulting mixture for 5 min. The reaction mixturewas heated at 95° C. for 20 min under a nitrogen atmosphere beforecooling to room temperature and evaporating the solvent in vacuo. Theresidue was purified by silica gel column chromatography using ethylacetate as eluent to provide 334 mg of A473.2. HPLC YMC S-5 4.6×33 mm (2min grad): retention time 1.72 min, M+H⁺=566.34.

A473.3:[7-[6-((S)-1-tert-Butoxycarbonylamino-3-methoxy-propyl)-pyridin-2-ylethynyl]-1-methyl-6-(2,2,2-trifluoro-acetylamino)-1H-imidazo[4,5-c]pyridin-4-yl]-methyl-carbamicacid tert-butyl ester

Trifluoroacetic anhydride (0.164 mL, 1.18 mmol) was added dropwise over5 min to a cooled (0° C.) solution of A473.2 (334 mg, 0.592 mmol) andtriethylamine (0.25 mL, 1.78 mmol) in THF (10 mL) under a nitrogenatmosphere. The cooling bath was removed after 10 min and the reactionmixture allowed to stir at room temperature for 1 h before evaporatingin vacuo. The residue was taken up in dichloromethane (50 mL) and washedwith saturated sodium bicarbonate solution (25 mL). The organic layerwas separated and dried (MgSO₄), then evaporated in vacuo to yield thecrude product A473.3 which was used immediately without furtherpurification (369 mg). HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 1.87 min, M+H⁺=662.32

A473.4(S)-7-(6-(1-tertbutyloxycarbonylamino-3-methoxypropyl)pyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-tert-butyloxycarbonylamine

Potassium carbonate (85 mg, 0.615 mmol) anddichlorobistriphenylphosphine palladium II (24 mg, 0.034 mmol) were eachadded in one portion to a solution of the trifluoroacetamide A473.3 (369mg, 0.56 mmol) in dimethylacetamide (6 mL) at room temperature under anitrogen atmosphere. The reaction was heated to 120° C. for 3 hrs beforeevaporating in vacuo and purifying by column chromatography using ethylacetate to yield A473.4 (283 mg, 90%). HPLC YMC S-5 4.6∴33 mm (2 mingrad): retention time 1.73 min, M+H⁺=566.32.

A473.5:(S)-7-(6-(1-amino-3-methoxypropyl)pyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

Trifluoroacetic acid in dichloromethane (20% solution, 10 mL) was addedin one portion to A473.4 (283 mg) and the resulting reaction mixture wasstirred at room temperature for 1 hr before evaporating in vacuo. Theresidue was partitioned between ethyl acetate (5 mL) and saturatedaqueous sodium hydrogen carbonate solution (5 mL). The aqueous phase wasextracted with ethyl acetate (2×10 mL) and the combined organics weredried (MgSO₄) and evaporated in vacuo to yield A473 (178 mg) as a tanpowder. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.33 min,M+H⁺=366.31.

Example A474(S)-2-methoxy-N-(3-methoxy-1-(6-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)propyl)acetamide

EDC (9 mg, 0.045 mmol) was added in one portion to a mixture ofmethoxyacetic acid (5 mg, 0.05 mmol), HOBt (7 mg, 0.045 mmol) and DIPEA(0.02 mL) in anhydrous DMF (0.5 mL) and the resulting mixture wasallowed to stir at room temperature for 30 min before addition of A473(15 mg, 0.041 mmol). The mixture was heated to 70° C. for 2 h in ascrew-capped vial before cooling to room temperature and evaporating invacuo. The residue was purified by preparative HPLC to yield amide A474(8 mg). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.30 min,M+H⁺=438.29

The examples in Table A18 were prepared in a manner similar to that forA474 by the reaction of A473 and the appropriate carboxylic acid. TABLEA18

HPLC Retention MS Ex. R Name (min) Reported A475 CH₃—(S)-N-(3-methoxy-1- 1.36 408.31 (6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b] pyridin-7- yl)pyridin-2-yl)propyl)acetamide A476

(S)-3-methoxy-N-(3- methoxy-1-(6-(1-methyl- 4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)propyl)propanamide 1.31 452.32 A477

(S)-2-methoxy-N-((S)-3- methoxy-1-(6-(1-methyl- 4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)propyl)propanamide 1.42 452.32 A478

(S)-N-(3-methoxy-1- (6-(1-methyl- 4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)propyl)-3- morpholinopropanamide 1.34 507.32 A479

(S)-2-(1H-imidazol-4-yl)- N-(3-methoxy-1- (6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2- yl)propyl)acetamide 1.27 488.30 A480

(S)-2-cyano-N- (3-methoxy-1- (6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)propyl)acetamide 1.36 433.29

Example A481(gammaR)-gamma-amino-6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinepropanoltrihydrochloride

Analogous chemistry utilized to prepare A469 was used to produce A481with (R)-stereochemistry (starting from D-valine methyl esterhydrochloride):

-   -   Column: Chiralpak AD 250×4.6 mm ID; 10 μm    -   Temperature: 35° C.    -   Mobil Phase: Hex/EtOH/DEA=20:80:0.1    -   Flow rate: 1.0 mL/min    -   Injection volume: 5˜15 μl    -   UV Detection: 368 nm        Retention time=6.7 min, 91.4 enantiomeric excess.

Example A482N-[(1R)-1-[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]-3-hydroxypropyl]-2-methoxy-acetamide

EDC (23 mg, 0.12 mmol) was added in one portion to a mixture ofmethoxyacetic acid (11 mg, 0.12 mmol), HOBt (16 mg, 0.12 mmol) and DIPEA(0.041 mL) in anhydrous DMF (2 mL) and the resulting mixture was allowedto stir at room temperature for 30 min before addition of A481 (50 mg,0.109 mmol). The mixture was heated to 70° C. for 2 h in a screw-cappedvial before cooling to room temperature and evaporating in vacuo. Theresidue was partitioned between ethyl acetate (5 mL) and water (2 mL).The separated aqueous layer was adjusted to a pH of 7-8 and extractedwith ethyl acetate (3×30 mL). The combined organics were dried (MgSO₄),evaporated in vacuo and purified by column chromatography (5% MeOH inEtOAc) to yield amide A482 (29 mg). HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 1.13 min, M+H⁺424.28

The examples in Table A19 were prepared in a similar manner to ExampleA482 utilizing A481 and the appropriate carboxylic acid. TABLE A19

HPLC Retention MS Ex. R Name (min) Reported A483 CH₃—N-[(1R)-1-[6-[1,6-dihydro-1- 1.11 394.30 methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-3-hydroxypropyl]-acetamide A484

N-[(1R)-1-[6-[1,6-dihydro-1- methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]-3- hydroxypropyl]-3-methoxy-propanamide 1.14 438.29

Example A485(S)-7-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A485.1:(S)-2-[(S)-1-(6-Bromo-pyridin-2-yl)-but-3-enylamino]-3-methyl-butyricacid methyl ester

Dimethyl zinc (2.0M in toluene, 25.5 mL, 51.0 mmol) was added toanhydrous THF (30 mL) under a nitrogen atmosphere and the solutioncooled to −78° C. Allylmagnesium bromide (1.0M in diethyl ether, 51 mL,51.0 mmol) was then added dropwise over 30 min and the solution allowedto stir at −78 C under a nitrogen atmosphere for 30 min. A solution ofthe imine [prepared in an analogous manner as example A469.1substituting D-Valine methyl ester hydrochloride] (15.2 g, 51.0 mmol) inTHF (60 mL) was then added dropwise to the zincate solution at −78° C.over 1 hr. The resulting reaction mixture was then allowed to stir foran additional 1 hr at −78° C. before quenching with 10% sodium hydrogencarbonate solution (200 mL) and warming to room temperature. The mixturewas diluted with water (50 mL) and extracted with diethyl ether (2×200mL), the combined organic phases were then dried (MgSO₄) and evaporatedin vacuo and purified by column chromatography using 9:1 hexane/ethylacetate to yield A485.1 (11.6 g).

A485.2:(S)-2-[(S)-1-(6-Bromo-pyridin-2-yl)-but-3-enylamino]-3-methyl-butan-1-ol

Lithium aluminium hydride (2.0M in THF, 17.05 mL, 34.1 mmol) was addeddropwise over 30 min to a cooled (−5° C.) solution of the ester A485.1(11.6 g, 34.1 mmol) in THF (100 mL) under a nitrogen atmosphere. Thereaction mixture was allowed to stir for 1 hr before quenching at −5° C.with water (1.3 mL), 15% aqeuous sodium hydroxide solution (1.3 mL) andwater (3.9 mL) each added dropwise. The mixture was then allowed to warmto room temperature before filtering and washing with diethyl ether (60mL). The filtrate was washed with water (30 mL) and the separatedorganic layer was dried (MgSO₄), evaporated in vacuo and purified bycolumn chromatography using 3:1 hexane/ethyl acetate as eluent to yieldA485.2 (5.8 g). HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.27min, M+H⁺=315.16.

A485.3: (S)-1-(6-Bromo-pyridin-2-yl)-but-3-enylamine

40% Aqueous methylamine solution (22 mL) followed by periodic acid(15.26 g in 100 mL of water) were each added in one portion to asolution of the alcohol X (5.8 g, 18.59 mmol) in methanol/THF (9:1 v/v,200 mL). The reaction mixture was stirred at room temperature for 3 hrsbefore adding water (90 mL). The methanol was removed in vacuo and theresidue extracted with diethyl ether (3×300 mL). The combined organiclayers were dried (MgSO₄) and evaporated in vacuo to yield A485.3 (3.5g, 83%) which was used immediately without further purification. HPLCYMC S-5 4.6×33 mm (2 min grad): retention time 0.92 min, M+H⁺=229.10

A485.4: [(S)-1-(6-Bromo-pyridin-2-yl)-but-3-enyl]-carbamic acidtert-butyl ester

Triethylamine (10.8 mL) and BOC-anhydride (3.6 g, 16.5 mmol) were eachadded in one portion to a cooled (0° C.) solution of the amine A485.3(3.5 g, 15.5 mmol) in anhydrous dichloromethane (200 mL) under anitrogen atmosphere. The reaction mixture was allowed to warm slowly toroom temperature overnight before quenching with aqueous saturatedsodium hydrogen carbonate solution (10 mL). The organic layer was dried(MgSO₄) and evaporated in vacuo t give a crude residue which waspurified by column chromatography using 9:1 hexane/ethyl acetate aseluent to yield A485.4 (4.0 g, 79%). HPLC YMC S-5 4.6×33 mm (2 mingrad): retention time HPLC YMC S-5 4.6×33 mm (2 min grad): retentiontime 1.95 min, M+H⁺−Bu^(tert)=273.11.

A485.5: [(S)-1-(6-Bromo-pyridin-2-yl)-4-hydroxy-butyl]-carbamic acidtert-butyl ester

9-BBN (0.5M in THF, 12.27 mL, 6.13 mmol) was added dropwise over 10 minto a solution of A485.4 (2.0 g, 6.13 mmol) in THF (40 mL) at roomtemperature under a nitrogen atmosphere. The reaction mixture wasallowed to stir at room temperature for 2 hrs before cooling to 0° C.and adding hydrogen peroxide (30%, 3.1 mL) and sodium hydroxide (3M, 3.1mL). The mixture was then heated to 50° C. for 1 hr before cooling toroom temperature. The aqueous layer was separated and extracted withdiethyl ether (2×30 mL), the combined organic layers dried (MgSO₄),evaporated in vacuo and purified by column chromatography using 1:1hexane/ethyl acetate as eluent to give A485.5 (1.52 g). HPLC YMC S-54.6×33 mm, 2 min gradient; ret. Time=1.69 min, M+H⁺−Boc=247.12

A485.6: [(S)-1-(6-Bromo-pyridin-2-yl)-4-methoxy-butyl]-carbamic acidtert-butyl ester

Sodium hydride (60% dispersion in oil, 150 mg, 3.63 mmol) was added inone portion to a solution of the alcohol A485.5 (1.0 g, 2.91 mmol) inanhydrous THF (15 mL) cooled to 0° C. under a nitrogen atmosphere. Thereaction mixture was stirred for 10 min before the dropwise addition ofmethyl iodide (0.221 mL, 2.91 mmol). The reaction mixture was allowed towarm slowly to room temperature overnight before quenching with water (5mL) and extracting diethyl ether (2×20 mL). The combined organics weredired (MgSO₄), evaporatred in vacuo and purified by columnchromatography using 4:1 hexane/ethyl acetate to yield A485.6 (900 mg).HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.95 min,M+Na⁺=383.18

A485.7:[(S)-4-Methoxy-1-(6-trimethylsilanylethynyl-pyridin-2-yl)-butyl]-carbamicacid tert-butyl ester

TMS-Acetylene (0.39 mL, 2.76 mmol) was added dropwise to A485.6 (0.9 g,2.51 mmol), CuI (24 mg, 0.13 mmol) and palladiumdichlorobistriphenylphosphine palladium II (117 mg, 0.17 mmol) intriethylamine (10 mL) at room temperature under a nitrogen atmosphere.The reaction mixture was stirred at room temperature overnight beforeevaporating in vacuo. Diethyl ether was added (20 mL) and the saltfiltered. The filtrate was evaporated in vacuo and purified by columnchromatography using 4:1 hexane:ethyl acetate to yield A485.7 (1.04 g).HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.22 min,M+H⁺=377.36

A485.8:{6-Amino-7-[6-((S)-1-tert-butoxycarbonylamino-4-methoxy-butyl)-pyridin-2-ylethynyl]-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl}-methyl-carbamicacid tert-butyl ester

Sodium hydroxide (2N, 2.8 mL) was added in one portion to theTMS-acetylene A485.7 (1.04, 2.77 mmol) in THF (20 mL) at roomtemperature. After stirring for 1 hr, the reaction mixture was dilutedwith water (20 mL) and extracted with diethyl ether (2×30 mL). Thecombined organics were dried (MgSO₄), evaporated in vacuo and purifiedby column chromatography using 4:1 hexane:ethyl acetate as eluent toyield [(S)-1-(6-Ethynyl-pyridin-2-yl)-4-methoxy-butyl]-carbamic acidtert-butyl ester (667 mg, 79%).

A1.12 (804 mg, 1.99 mmol), dichlorobis(triphenylphosphine)palladium (93mg, 0.14 mmol),[(S)-1-(6-Ethynyl-pyridin-2-yl)-4-methoxy-butyl]-carbamic acidtert-butyl ester (667 mg, 2.19 mmol) and diisopropylamine (7 mL) wereeach added to N,N-dimethylformamide (5 mL) and nitrogen bubbled throughthe resulting mixture for 5 min. The reaction mixture was heated at 95°C. for 20 min under a nitrogen atmosphere before cooling to roomtemperature and evaporating the solvent in vacuo. The residue waspurified by silica gel column chromatography using ethyl acetate aseluent to provide 1.09 g of A485.8. HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 3.45 min, M+H⁺=580.25

A485.9:[7-[6-((S)-1-tert-Butoxycarbonylamino-4-methoxy-butyl)-pyridin-2-ylethynyl]-1-methyl-6-(2,2,2-trifluoro-acetylamino)-1H-imidazo[4,5-c]pyridin-4-yl]-methyl-carbamicacid tert-butyl ester

Trifluoroacetic anhydride (0.52 mL, 3.77 mmol) was added dropwise over 5min to a cooled (0 C) solution of aminopyridine A485.8 (1.09 mg, 1.88mmol) and triethylamine (0.79 mL, 5.64 mmol) in THF (30 mL) under anitrogen atmosphere. The cooling bath was removed after 10 min and thereaction mixture allowed to stir at room temperature for 1 hr beforeevaporating in vacuo. The residue was taken up in dichloromethane (50mL) and washed with saturated sodium bicarbonate solution (25 mL). Theorganic layer was separated and dried (MgSO₄), then evaporated in vacuoto yield the crude product A485.9 which was used immediately withoutfurther purification (1.23 g). HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 3.52 min, M+H⁺=676.30

A485.10:(S)-7-(6-(1-tert-butyloxycarbonylamino-4-methoxybutyl)pyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-tert-butyloxycarbonylamine

Potassium carbonate (280 mg, 2.0 mmol) and dichlorobistriphenylphosphinepalladium II (80 mg, 0.109 mmol) were each added in one portion to asolution of the trifluoroacetamide A485.9 (1.23 g, 1.82 mmol) indimethylacetamide (20 mL) at room temperature under a nitrogenatmosphere. The reaction was heated to 120° C. for 3 hrs beforeevaporating in vacuo and purifying by column chromatography using ethylacetate to yield A485.10 (809 mg). HPLC YMC S-5 4.6×33 mm (2 min grad):retention time 3.45 min, M+H⁺=580.25

A485.11:(S)-7-(6-(1-amino-4-methoxybutyl)pyridin-2-yl)-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

Trifluoroacetic acid in dichloromethane (20% solution, 10 mL) was addedin one portion to A485.10 (809 mg) and the resulting reaction mixturewas stirred at room temperatuire for 1 hr before evaporating in vacuo.The residue was partitioned between ethyl acetate (5 mL) and saturatedsodium hydrogen carbonate solution (5 mL). The aqueous phase wasextracted with ethyl acetate (2×10 mL) and the combined organics weredried (MgSO₄) and evaporated in vacuo to yield A485 (530 mg) as a tanpowder. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 1.073 min,M+H⁺=380.47

Amine A485 was reacted with carboxylic acids in an analogous amideformation procedure to prepare compounds in Table A20. TABLE A20

HPLC Retention MS Ex. R Name (min) Reported A486 CH₃—(S)-N-(4-methoxy-1-(6-(1- 1.45 422.34 methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)acetamide A487

(S)-2-methoxy-N-(4- methoxy-1-(6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)acetamide 1.46 452.32 A488

(S)-N-(4-methoxy-1-(6-(1- methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)-3-morpholinopropanamide 1.39 521.33 A489

(S)-2-methoxy-N-((S)-4- methoxy-1-(6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)propanamide 1.51 466.34 A490

(S)-2-cyano-N-(4-methoxy-1- (6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)acetamide 1.45 447.32 A491

(S)-N-((S)-4-methoxy-1-(6- (1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)butyl)-5- oxopyrrolidine-2- carboxamide 1.39 491.28 A492

3-hydroxy-N-((S)-4-methoxy- 1-(6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)butanamide 1.40 466.34 A493

(S)-2-hydroxy-N-((S)-4- methoxy-1-(6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)-3-methylbutanamide 1.52 480.34 A494

(S)-N-(4-methoxy-1-(6-(1- methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)picolinamide 1.55 485.27 A495

2-acetamido-N-((S)-4- methoxy-1-(6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)-3-methylbutanamide 1.47 521.34 A496

1-acetyl-4-hydroxy-N-((S)-4- methoxy-1-(6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2- yl)butyl)pyrrolidine-2- carboxamide 1.30 535.31 A497

(S)-2-(dimethylamino)-N-(4- methoxy-1-(6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)acetamide 1.35 465.36 A498

(S)-N-(4-methoxy-1-(6-(1- methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)pyrazine-2- carboxamide 1.47 486.28 A499

2-hydroxy-N-((S)-4-methoxy- 1-(6-(1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)butyl)-4-methylpentanamide 1.49 494.32 A500

(S)-3-chloro-2-hydroxy-N-(4- methoxy-1-(6-(1-methyl-4-(methylamino)-1,6- dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2- yl)butyl)benzamide 1.82 534.25 A501

(S)-N-(4-methoxy-1-(6-(1- methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)butyl)-2-(1- methyl-1H-imidazol-4- yl)acetamide 1.35502.32

Examples A502-A511

Examples A502-A511 was prepared in a manner similar to example A1. Thusintermediate A1.12 was subjected to a what is commonly referred to as aSonoghasira type coupling (as described in detail for the preparation ofA1.13, and conducted in a similar manner) with acetylenes which areeither commercially available, or readily prepared (as described forstep A2.1 and A2.2). The acetylene were cyclized to the examples inTable A2 in a manner described in detail in step A1.14 TABLE A21

HPLC Retention MS Ex. R Name (min) Reported A502

7-(2-fluorophenyl)-1,6- dihydro-N,1-dimethyl- imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine 2.28 296.25 A503

7-cyclopropyl-1,6-dihydro- N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 1.72 242.33 A504

7-(3-chloro-2-fluorophenyl)- 1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 2.65 330.26 A505

7-(3,4-difluorophenyl)-1,6- dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 2.59 314.29 A506

1,6-dihydro-N,1-dimethyl-7- (3,4,5-trifluorophenyl)-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 2.82 332.32 A507

1,6-dihydro-N,1-dimethyl-7- [3-(methylthio)phenyl]-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 2.71 324.33 A508

1,6-dihydro-N,1-dimethyl-7- [3-(methylsulfonyl)phenyl]-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 2.04 356.35 A509

7-(3,4-difluoro-5- methoxyphenyl)-1,6-dihydro- N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 2.72 344.28 A510

1,6-dihydro-N,1-dimethyl-7- (2,4,5-trifluorophenyl)-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 2.59 332.32 A511

7-(3-chloro-5-fluorophenyl)- 1,6-dihydro-N,1-dimethyl-imidazo[4,5-d]pyrrolo[2,3- b]pyridin-4-amine 2.99 330.25

Example A5121,6-dihydro-N,1-dimethyl-7-[3-(methylsulfinyl)phenyl]-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A512.1: trimethyl((3-(methylthio)phenyl)ethynyl)silane

Was prepared as described for step A2.1 HPLC: 94%, retention time: 4.303minute (condition A). LC/MS (M+H)⁺=221.2.

A512.2: (3-ethynylphenyl)(methyl)sulfane

Was prepared as described in step A2.2. HPLC: 90%, retention time: 3.418minute

A512.3: tert-butyl6-amino-1-methyl-7-((3-(methylthio)])phenyl)ethynyl)-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

Was prepared in a similar manner to A1.13

HPLC: 92%, retention time: 3.555 minute (condition B) LC/MS(M+H)⁺=424.3.

A512.4: tert-butylmethyl(1-methyl-7-(3-(methylthio)phenyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl)carbamate

Was prepared in a similar manner to A2.4

HPLC: 98%, retention time; (condition B) 3.371 minute LC/MS(M+H)⁺=424.4, ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.90 (1H, s), 7.57 (1H, s),7.43-7.48 (1H, m), 7.39 (1H, t, J=7.63 Hz), 7.23 (1H, s), 7.00 (1H, d,J=2.54 Hz), 4.15 (3H, s), 3.52 (3H, s), 2.56 (3H, s), 1.46 (9H, s).

A512.5:1,6-dihydro-N,1-dimethyl-7-[3-(methylsulfinyl)phenyl]-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A solution of A512.4 (46 mg, 0.109 mmol) in acetic acid (0.5 ml) at 0-5°C. was added 30% H₂O₂ (41 uL, 0.4 mmol) and warmed up to RT. Thereaction mixture was concentrated to yield a crude product which wasdiluted with dichloromethane (4 ml). The organic phase was washed withsaturated aqueous NaHCO₃ solution (1 ml), water (1 ml), brine (1 ml) andthe organic layer was dried over sodium sulfate. The mixture wasfiltered and the solvent evaporated under reduced pressure to yield aBoc protected intermediate which was dissolved in CH₂Cl₂ (1 ml) wasadded TFA (0.5 ml) dropwise at 0-5° C. which was warmed up to RT andstirred for 1 hr. The reaction mixture was concentrated and trituratedwith diethyl ether (˜5 ml) for ˜10 minutes. The solid was collected asA512. HPLC: >95%, retention time: 1.947 minute LC/MS (M+H)⁺=340.3,¹H-NMR (400 MHz, CD₃OD) δ ppm 8.14 (1H, s), 8.02 (1H, s), 7.88 (1H, d,J=7.63 Hz), 7.47-7.63 (2H, m), 7.24 (1H, s), 4.09 (3H, s), 3.19 (3H, s),2.80 (3H, s).

Examples A513 and A5141,6-dihydro-N,1-dimethyl-7-[3-(methylsulfinyl)phenyl]-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A512 (43 mg, 0.095 mmol) was subjected to chiral separation to yieldA513 (9.2 mg, 57%). HPLC: 98%, retention time: 1.845 minute (conditionA). Chiral HPLC: 100% ee. retention time: 8.17 minute (condition H).LC/MS (M+H)⁺=340. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.06 (1H, s), 7.96(1H, d, J=7.63 Hz), 7.89 (1H, s), 7.55 (1H, t, J=7.88 Hz), 7.44 (1H, d,J=7.63 Hz), 7.22 (1H, d, J=2.54 Hz), 6.64 (1H, d, J=5.09 Hz), 4.10 (1H,q, J=5.26 Hz), 4.02 (3H, s), 3.15 (1H, d, J=5.09 Hz), 2.97 (3H, d,J=4.58 Hz), 2.81 (3H, s) and A514 (9 mg, 56%). HPLC: 94%, retentiontime: 1.873 minute (condition A). Chiral HPLC: 100% ee. retention time:10.53 minute (condition H). LC/MS (M+H)⁺=340. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 8.06 (1H, s), 7.96 (1H, d, J=8.14 Hz), 7.89 (1H, s), 7.55 (1H, t,J=7.63 Hz), 7.41-7.47 (1H, m), 7.22 (1H, d, J=2.03 Hz), 6.60-6.67 (1H,m), 4.10 (1H, q, J=5.26 Hz), 4.02 (3H, s), 3.15 (1H, d, J=5.09 Hz), 2.97(3H, d, J=4.58 Hz), 2.81 (3H, s).

Example A515N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]-3-methoxy-propanamide

3-methoxypropionic acid (7.34 uL, 0.075 mmol), HOBt (17 mg, 0.125 mmol),and diisopropylethylamine (0.148 ml) was dissolved in CH₃CN (1 ml). EDCI(30 mg, 0.167 mmol) was added and the reaction mixture was stirred at RTfor 5 minutes. A293.5 (30 mg, 0.071 mmol) was added and the reactionmixture heated to 80° C. for 30 minutes. The reaction mixture wasconcentrated and purified on prep. HPLC (condition G) to yield the Bocprotected intermediate.

The intermediate was dissolved in CH₂Cl₂ (0.25 ml) and added TFA (0.25ml) dropwise at 0-5° C. which was warmed up to RT and stirred for 30mintes. The reaction mixture was concentrated to yield A515 (10 mg,27%). HPLC: 97%, retention time: 2.190 minute (condition B). LC/MS(M+H)⁺=411.3, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.48 (1H, s), 8.11 (1H, s),7.42 (1H, s), 7.27-7.37 (1H, m), 7.13 (1H, s), 6.91 (1H, d, J=7.63 Hz),4.36 (2H, s), 4.06 (3H, s), 3.60 (2H, t, J=6.10 Hz), 3.25 (3H, s), 3.16(3H, s), 2.43 (2H, t, J=5.85 Hz).

Example A516N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]-4-morpholinecarboxamide

A293.5 (57 mg, 0.134 mmol), 1,1′-carbonyldiimidazole (44 mg, 0.268mmol), and triethylamine (34 mg, 0.336 mmol) were dissolved in a mixtureof dichloroethane (1 ml)/DMF (0.25 ml) and stirred at RT for 30 minutes.Morpholine (0.25 ml, 2.86 mmol) was added and the reaction mixture washeated to 80° C. for 30 minutes. The solvent was concentrated underreduced pressure and the residue purified by prep. HPLC (condition G) toyield the Boc protected intermediate.

The product was dissolved in CH₂Cl₂ (0.5 ml) and TFA (0.5 ml) was addeddropwise at 0-5° C. which was warmed up to RT and stirred for 30 mintes.The reaction mixture was concentrated under reduced pressure to yieldA516 (23.3 mg, 32%). HPLC: 97%, retention time: 2.315 minute (conditionB). LC/MS (M+H)⁺=438.4, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.11 (1H, s), 7.41(1H, s), 7.30 (1H, d, J=10.17 Hz), 7.12 (1H, s), 6.89 (1H, d, J=8.65Hz), 4.32 (2H, s), 4.05 (3H, s), 3.53-3.62 (4H, m), 3.28-3.37 (4H, m),3.16 (3H, s).

Examples A517-A525

Examples A517-A525 was prepared in a manner similar to example A516.TABLE A22

HPLC Retention MS Ex. R Name (min) Reported A517

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N′-(2-methoxyethyl)-urea 2.12 426.34 A518

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N′-(2-hydroxyethyl)-urea 2.01 412.32 A519

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-1-piperazinecarboxamide 1.98 437.39 A520 CH₃NH—N-[[3-[1,6-dihydro-1-methyl- 2.18 382.36 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N′- methyl-ureaA521

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-4- hydroxy-1-piperidinecarboxamide 2.14 452.38 A522

N-(2-cyanoethyl)-N′-[[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]-N- methyl-urea 2.12 435.36 A523

N′-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N-(2-methoxyethyl)-N-methyl-urea 2.30 440.37 A524

3-(acetylamino)-N-[[3-[1,6- dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]-1- pyrrolidinecarboxamide 2.09 479.33 A525

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-3- hydroxy-1-pyrrolidinecarboxamide 2.08 485.35

Examples A526-A528

Examples A526 was prepared in a manner similar to example A515. ExamplesA527 (retention time: 5.99 minute) and A528 (retention time: 13.5minute) were separated by chiral chromatography of A526. Chiral HPLC:Column ChiralCEL OD 10 um 4.6×250 mm; Percent B=35% Isocratic; Flowrate=2 ml/min; Solvent A=CO₂; Solvent B MeOH—0.1% DEA. TABLE A23

HPLC Reten- MS tion Re- Ex. R Name (min) ported A526

Racemic-N-[[3- [1,6-dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-3-morpholinecarboxamide 1.62 438 A527

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-3-morpholinecarboxamide- faster eluting enantiomer 1.67 438 A528

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-3-morpholinecarboxamide- slower eluting enantiomer 1.67 438

Example A529N″-cyano-N-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]-N′-methyl-guanidine

A solution of A293 (32.5 mg, 0.059 mmol), triethylamine (9 uL, 0.065mmol) and phenyl cyanocarbonimidate (14.3 mg, 0.06 mmol) in ethanol (1ml) was heated to 100° C. for 10 minutes under micromave. Methylamine(0.185 ml, 0.37 mmol, 2M in THF)) was added and then it was heated to120° C. for 15 minutes under microwave. The solid was collected as A529(13.8 mg, 58%), HPLC: 95%, retention time: 2.322 minute (condition B).LC/MS (M+H)⁺=406, ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.76 (1H, s), 7.39 (1H,s), 7.29 (1H, d, J=10.17 Hz), 6.96 (1H, s), 6.76 (1H, d, J=8.14 Hz),4.36 (2H, s), 3.98 (3H, s), 3.01 (3H, s), 2.74 (3H, s).

Examples A530-537

Examples A530-A537 was prepared in a manner similar to example A529.TABLE A24

HPLC Retention MS Ex. R Name (min) Reported A530

N′-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-4-morpholinecarboximidamide 2.44 462.34 A531

N″-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N′-(2-methoxyethyl)-guanidine 2.45 450.29 A532

N″-cyano-N′-[[3-[1,6- dihydro-1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N-(2-(methoxyethyl)-N-methyl- guanidine 2.49 464.34 A533

N-[1-[(E)-(cyanoimino)[[[3- [1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]amino]methyl]-3-pyrrolidinyl]- acetamide 2.34503.34 A534

N′-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-4- hydroxy-1-piperidinecarboximidamide 2.34 476.36 A535

N″-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N′-(2-hydroxyethyl)-guanidine 2.30 436.36 A536

N′-cyano-N-[[3-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-4- methyl-1-piperazinecarboximidamide 2.09 475.36 A537

N″-cyano-N-cyclopropyl-N′- [[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]- guanidine 2.46 432.35

Examples A538-540

Examples A538-A540 was prepared in a manner similar to example A529starting with A215. TABLE A25

HPLC Reten- MS tion Re- Ex. R Name (min) ported A538

N′-cyano-N-[[6-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-4-morpholinecarboximidamide 1.94 445.28 A539

N″-cyano-N-cyclopropyl-N′- [[6-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]- guanidine 2.00 415.29 A540

N″-cyano-N-[[6-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N′-(2-hydroxyethyl)-guanidine 1.90 419.30

A541[[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]amino]oxo-aceticacid, methyl ester

A541.1: Methyl2-(3-(4-(tert-butoxycarbonyl(methyl)amino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzylamino)-2-oxoacetate

A solution of A293.5 (85 mg, 0.2 mmol) and triethylamine (35 uL, 0.25mmol) in dichloromethane (2 mL) at 0-5° C. was added methylchlorooxoacetate (20 uL, 0.22 mmol) and the reaction mixture was warmedup to room temperature and stirred for 30 minutes. The reaction mixturewas concentrated and purified on silica gel column with CH₂Cl₂/MeOH(20/1) to yield A541.1 (78 mg, 76%). HPLC: 98%, retention time: 2.633minute (condition B). LC/MS (M+H)⁺=511, ¹H-NMR (400 MHz, CDCl₃) δ ppm7.95 (1H, s), 7.82 (1H, s), 7.42 (1H, s), 7.22-7.32 (1H, m), 6.90-7.06(1H, m), 6.90-7.02 (2H, m), 4.59 (2H, d, J=6.10 Hz), 4.11 (3H, s),3.88-4.00 (3H, m), 3.52 (3H, s).

A541.2:[[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]amino]oxo-aceticacid, methyl ester

A541 was prepared in a similar manner as described for step A2.5. HPLC:99%, retention time: 2.283 minute (condition B). LC/MS (M+H)⁺=411,¹H-NMR (400 MHz, CD₃OD) δ ppm 8.15 (1H, s), 7.47 (1H, s), 7.39 (1H, s),7.17 (1H, s), 6.96 (1H, s), 4.42-4.49 (2H, m), 4.08 (3H, s), 3.82 (3H,s), 3.19 (3H, s).

Example A542[[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]amino]oxo-aceticacid

A542.1:2-(3-(4-(tert-butoxycarbonyl(methyl)amino)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzylamino)-2-oxoaceticacid

A solution of A541.1 (67.2 mg, 0.134 mmol) and 1N NaOH (0.28 ml, 0.28mmol) in MeOH (2.8 ml) was heated to 100° C. for 15 minutes undermicromave and the reaction mixture was concentrated to yield a crudeproduct. It was added water (1 ml) and acidified with 1N HCl solutionuntil PH about 2 at 0-5° C. The solid was collected as A542.1 (60.5 mg,93%). HPLC: 97%, retention time: 2.558 minute (condition B). LC/MS(M+H)⁺=497, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.26 (1H, s), 7.68 (1H, s),7.56 (1H, d, J=10.68 Hz), 7.34 (1H, s), 7.06 (1H, s), 4.53 (2H, s), 4.22(3H, s), 3.40 (3H, s), 1.39 (9H, s).

A542.2:[[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]amino]oxo-aceticacid

A solution of A542.1 (10 mg, 0.02 mmol) in CH₂Cl₂ (0.25 ml) was addedTFA (0.25 ml) dropwise at 0-5° C. which was warmed up to RT and stirredfor 10 minutes. The reaction mixture was concentrated to yield A542 (9.6mg, 93%). HPLC: >85%, retention time: 2.025 minute (condition B). LC/MS(M+H)⁺=397, ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 12.09 (1H, s), 9.33-9.46(1H, m), 8.40 (1H, s), 7.52-7.69 (3H, m), 7.28 (1H, s), 6.85-6.99 (1H,m), 4.37 (2H, d, J=6.10 Hz), 4.09 (3H, s), 3.04 (3H, s).

Example A543N-cyclopropyl-N′-[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]-ethanediamide

A solution of A542.1 (10 mg, 0.02 mmol), HOBt (4.86 mg, 0.036 mmol),diisopropylethylamine (0.042 ml) in CH₃CN (1 ml) was added EDCI (9 mg,0.047 mmol) and then the reaction mixture was stirred at RT for 5minutes. It was added cyclopropylamine (1.26 mg, 0.022 mmol) and heatedto 80° C. for 30 minutes. The reaction mixture was concentrated andpurified on prep. HPLC (condition G) to yield a product.

The product was dissolved in CH₂Cl₂ (0.25 ml) and added TFA (0.25 ml)dropwise at 0-5° C. which was warmed up to RT and stirred for 30minutes. The reaction mixture was concentrated to yield A543 (6.6 mg,60%). HPLC: >98%, retention time: 2.220 minute (condition B). LC/MS(M+H)⁺=436, ¹H-NMR (400 MHz, DMSO-d6) δ ppm 12.04 (1H, s), 9.25-9.39(1H, m), 8.82 (1H, d, J=5.09 Hz), 8.33 (1H, s), 7.51-7.69 (2H, m), 7.25(1H, s), 6.89 (1H, s), 4.35 (2H, d, J=6.61 Hz), 4.08 (3H, s), 3.02 (3H,s), 2.76 (1H, dd, J=16.79, 5.09 Hz), 0.53-0.72 (4H, m)

Examples A544-A546

Examples A544-A546 was prepared in a manner similar to example 543 usingthe appropriate amine. TABLE A26

HPLC Reten- MS tion Re- Ex. R Name (min) ported A544

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]- alpha-oxo-4-morpholineacetamide 2.86 466.31 A545

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]- alpha-oxo-1-piperazineacetamide 1.97 465.30 A546

N-[[3-[1,6-dihydro-1-methyl- 4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 5-fluorophenyl]methyl]-N′-(2-hydroxyethyl)- ethanediamide 1.90 419.30

Examples A547-A50

Examples A547-A50 was prepared in a manner similar to example A529starting with A215. TABLE A27

HPLC Retention MS Ex. R Name (min) Reported A547 CH₃NH—N″-cyano-N-[[6-[1,6-dihydro- 1.96 389.31 1-methyl-4-(methylamino)imidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl]-2-pyridinyl]methyl]-N′- methyl-guanidine A548

N″-cyano-N-[[6-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N′-(2-hydroxypropyl)-guanidine 2.06 433.32 A549

N″-cyano-N-[[6-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N′-(2-methoxyethyl)-guanidine 2.12 433.32 A550

N″-cyano-N-[[6-[1,6-dihydro- 1-methyl-4- (methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]- 2-pyridinyl]methyl]-N′-(2,3-dihydroxypropyl)-guanidine 2.06 449.28

Example A551N-[(1E)-[[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]amino][(2-methoxyethyl)amino]methylene]-urea

A solution of A293.3 (30 mg, 0.071 mmol) and phenyl cyanocarbonimidate(17.4 mg, 0.071 mmol) in n-butanol (1 ml) was heated to 100° C. for 10minutes under micromave. A portion of 2-methoxyethylamine (200 uL) wasadded and then it was heated to 120° C. for 15 minutes under microwave.The reaction mixture was concentrated and puritfied on prep. HPLC(condition G) to yield the Boc protected intermediate which wasdissolved in CH₂Cl₂ (0.25 ml) and added TFA (0.25 ml) dropwise at 0-5°C. which was warmed up to RT and stirred for 30 mintes. The reactionmixture was concentrated to yield A551 (11 mg, 33%). HPLC: >95%,retention time: 1.758 minute (condition A). LC/MS (M+H)⁺=468, ¹H-NMR(400 MHz, DMSO-d₆) δ ppm 9.58 (1H, s), 8.14 (1H, s), 7.47-7.71 (3H, m),7.26 (1H, s), 6.96 (2H, s), 4.58 (2H, s), 4.04 (3H, s), 3.50 (4H, m),3.25 (3H, s), 3.00 (3H, s).

Example A552N-[(1Z)-[[[3-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluorophenyl]methyl]amino](methylamino)methylene]-urea

Example A552 was prepared in a similar manner to A551. HPLC: 96%,retention time: 1.918 minute (condition B). LC/MS (M+H)⁺=424 ¹H-NMR (400MHz, CD₃OD) δ ppm 8.02 (1H, s), 7.38-7.53 (2H, m), 7.14 (1H, s), 6.92(1H, d, J=9.16 Hz), 4.51 (2H, s), 4.03 (3H, s), 3.13 (3H, s), 2.86-2.96(3H, s).

Example A553 and A553aN,1-dimethyl-7-(3-vinylphenyl)-1,6-dihydroimidazo[4,5-dipyrrolo[2,3-b]pyridin-4-amineandN,1-dimethyl-7-(3′-vinylbiphenyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A553.1: tert-butyl6-amino-7-((3-bromophenyl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

During the production of A75.1 the product was found to contain ˜20% ofA553.1a. The mixture of products was used in the next step withoutfurther purification.

A75.2 was prepared in a similar manner as described previously HPLC:82%, retention time. LC/MS (M+H)⁺=458. The product contains ˜16% ofA553.2a. The mixture of products was used in the next step withoutfurther purification.

A553.3: tert-butylmethyl(1-methyl-7-(3-vinylphenyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl)carbamate

A solution of A75.2 (444 mg, 0.974 mmol), triphenylphosphine (106 mg,0.403 mmol), tetrakis(triphenylphosphine)Palladium(0) (106 mg, 0.098mmol) and vinyltributyltin (0.314 ml, 1.07 mmol) in DMF (6 ml) washeated to 120° C. for 15 minutes under microwave. The reaction mixturewas concentrated and purified on silica gel column with EtOAC to yield amixture of A553.3 and A553.3a. The mixture of was purified on prep HPLC(condition G) to yield pure A553.3 (239 mg, 47%). HPLC: 99%, retentiontime: 3.328 minute (condition A). LC/MS (M+H)⁺=404. ¹H-NMR (400 MHz,CD₃OD) δ ppm 7.92 (1H, s), 7.74 (1H, dd, J=6.36, 2.80 Hz), 7.53-7.60(1H, m), 7.45-7.51 (1H, m), 7.36-7.41 (2H, m), 7.34 (1H, s), 6.76 (1H,dd, J=17.80, 10.68 Hz), 5.87 (1H, d, J=18.31 Hz), 5.26 (1H, d, J=11.19Hz), 4.29 (3H, s), 3.39 (3H, s), 1.39 (9H, s). It also afforded A553.3a(30 mg). HPLC: 99%, retention time: 4.136 minute (condition A). LC/MS(M+H)⁺=504. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.56 (1H, s), 7.97 (1H, s),7.77 (1H, d, J=7.63 Hz), 7.61 (1H, s), 7.43-7.56 (3H, m), 7.38-7.43 (1H,m), 7.34 (1H, t, J=7.63 Hz), 7.11 (1H, d, J=2.03 Hz), 6.71 (1H, dd,J=17.55, 10.94 Hz), 5.81 (1H, d, J=17.29 Hz), 5.32 (1H, d, J=11.19 Hz),4.25 (3H, s), 3.56 (3H, s), 1.51 (9H, s).

A553.4:N,1-dimethyl-7-(3-vinylphenyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A553 was prepared in a similar manner as step A2.5. HPLC: >95%,retention time: 2.580 minute (condition A). LC/MS (M+H)⁺=304. ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.08 (1H, s), 7.74 (1H, s), 7.54-7.59 (1H, m),7.29-7.35 (2H, m), 7.11 (1H, s), 6.72 (1H, dd, J=17.80, 11.19 Hz), 5.82(1H, d, J=17.80 Hz), 5.22 (1H, d, J=10.68 Hz), 4.06 (3H, s), 3.17 (3H,s).

A553.5:N,1-dimethyl-7-(3′-vinylbiphenyl-3-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A553a was prepared in a similar manner as step A2.5 HPLC: 96%, retentiontime: 3.941 minute (condition A). LC/MS (M+H)⁺=404. ¹H-NMR (400 MHz,CD₃OD) δ ppm 8.06 (1H, s), 7.86 (1H, s), 7.68 (1H, s), 7.50 (1H, s),7.31-7.40 (4H, m), 7.26 (1H, t, J=7.63 Hz), 7.15 (1H, s), 6.66 (1H, dd,J=17.80, 10.68 Hz), 5.75 (1H, d, J=17.80 Hz), 5.21 (1H, d, J=1.19 Hz),4.05 (3H, s), 3.16 (3H, s)

Example A554 Racemic1-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethane-1,2-diol

A554.1: tert-butyl7-(3-(1,2-dihydroxyethyl)phenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of A553.3 (110 mg, 0.273 mmol) in THF (4 mL) at 0-5° C. wasadded water (1 mL), 4-methylmorpholine-N-oxide (0.217 ml, 0.105 mmol; 50wt % in water), followed by OSO₄ (0.231 ml; 2.5% in isopropanol). Thereaction mixture was warmed up to RT and stirred for 4 hrs. The reactionwas quenched with saturated NaHSO₃ solution (6 mL) which was extractedwith EtOAC (10 mL×2). The combined organic phases was concentrated togive a crude product. It was added water (10 m]L) and stirred for 5minutes. The solid was collected as A554.1 (70 mg, 59%). HPLC: 94%,retention time: 2.278 minute (condition A). LC/MS (M+H)⁺=438. ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.00 (1H, s), 7.81 (1H, s), 7.69 (1H, d, J=8.14Hz), 7.35 (1H, t, J=7.63 Hz), 7.26 (1H, d, J=7.63 Hz), 7.16 (1H, s),4.66-4.70 (1H, m), 4.09 (3H, s), 3.55-3.64 (2H, m), 3.28 (3H, s), 1.28(9H, s).

A554.2:1-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethane-1,2-diol

A suspension solution of A554.1 (70 mg, 0.16 mmol) in CH₂Cl₂ (5 ml) at0-5° C. was added 4N HCl in dioxane (0.5 ml, 2 mmol) dropwise. Thereaction mixture was warmed up to RT and stirred for 1 hrs. The solidwas collected as A554 (55 mg, 92%). HPLC: 94%, retention time: 1.670minute (condition A). LC/MS (M+H)⁺=338. ¹H-NMR (400 MHz, CD₃OD) δ ppm8.10 (1H, s), 7.68 (1H, s), 7.56 (1H, d, J=7.63 Hz), 7.33 (1H, t, J=7.63Hz), 7.25 (1H, d, J=7.63 Hz), 7.07 (1H, s), 4.66 (1H, dd, J=6.87, 4.83Hz), 4.05 (3H, s), 3.53-3.62 (2H, m), 3.16 (3H, s)

Examples A555 and A5561-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethane-1,2-diol

A554 (55 mg, 0.147 mmol) was subjected to chiral separation (ChiralcelOJ 250×30 mm ID; 5 um, MeOH/IPA/DEA=50:50:0.1; 16 ml/min) to yield A555(21.8 mg, 87%). HPLC: >95%, retention time: 1.690 minute (condition A).Chiral HPLC: >99.9% ee. retention time: 9.957 minute (Chiralcel OJ 10 um4.6×250 mm; MeOH/IPA/DEA=50:50:0.1; 0.7 ml/min). LC/MS (M+H)⁺=338, ¹HNMR (500 MHz, CD₃OD) δ ppm 7.78 (1H, s), 7.68 (1H, s), 7.56 (1H, d,J=7.70 Hz), 7.28 (1H, t, J=7.70 Hz), 7.15 (1H, d, J=7.70 Hz), 6.93 (1H,s), 4.66 (1H, dd, J=7.15, 4.67 Hz), 4.00 (3H, s), 3.56-3.64 (2H, m),3.03 (3H, s) and A556 (18.2 mg, 73%). HPLC: >95%, retention time: 1.687minute (condition A). Chiral HPLC: 96.8% ee. retention time: 18.21minute (Chiralcel OJ 10 um 4.6×250 mm; MeOH/IPA/DEA=50:50:0.1; 0.7ml/min). LC/MS (M+H)⁺=338, ¹H NMR (500 MHz, CD₃OD) δ ppm 7.78 (1H, s),7.68 (1H, s), 7.57 (1H, d, J=7.70 Hz), 7.28 (1H, t, J=7.70 Hz), 7.15(1H, d, J=7.70 Hz), 6.93 (1H, s), 4.66 (1H, dd, J=7.29, 4.81 Hz), 4.01(3H, s), 3.46-3.72 (2H, m), 3.03 (3H, s).

Example A557(R)-2-amino-2-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethanol

A557.1:(R)-2-tert-butyloxycarbonylamino-2-(3-(1-methyl-4-(N-methyl-tert-butyloxycarbonylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethanol

A solution of tert-butyl carbamate (17.6 mg, 0.15 mmol) in n-propanol(0.2 ml) was added 1N NaOH solution (0.15 ml, 0.15 mmol), water (0.15ml), followed by t-BuOCl (17 uL, 0.15 mmol) and stirred at RT for 20minutes. The reaction mixture was cooled to 0-5° C. (DHQ)₂PHAL (1.95 mg,0.0025 mmol) in n-propanol (0.16 ml) was added and then A553.3 (20 mg,0.05 mmol) in n-propanol (0.4 ml) was added. Finally, to the reactionmixture was added K₂OsO₄o2H₂O (0.74 mg, 0.002 mmol) at 0-5° C. The colorof solution was changed from faint yellow to green and then to yellow.The reaction mixture was stirred for 2 hrs from at 0° C. to at RT andthe reaction was quenched with saturated NaHSO₃ solution (1 mL) andstirred for 15 minutes which was extracted with EtOAC (1 mL×3). Thecombined organic phases was washed with water (1 mL), brine (1 mL) andthe organic layer was dried over sodium sulfate. Filtration andconcentration to yield a crude product. It was purified on silica gelcolumn with EtOAc/MeOH (20/1) to yield as A557.1 (11.6 mg, 43%). HPLC:90%, retention time: 3.040 minute (condition A). LC/MS (M+H)⁺=537. ¹HNMR (400 MHz, CD₃OD) δ ppm 8.00 (1H, s), 7.74 (1H, s), 7.68 (1H, d,J=7.63 Hz), 7.34 (1H, t, J=7.63 Hz), 7.2.0 (1H, d, J=7.63 Hz), 7.16 (1H,s), 4.61-4.67 (1H, m), 4.10 (3H, s), 3.58-3.71 (2H, m), 3.28 (3H, s),1.34 (9H, s), 1.28 (9H, s).

A557.2:(R)-2-amino-2-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethanol

A suspension solution of A557.1 (11.6 mg, 0.022 mmol) in CH₂Cl₂ (1 ml)at 0-5° C. was added 4N HCl in dioxane (0.4 ml, 1.6 mmol) dropwise. Thereaction mixture was warmed up to RT and stirred for 20 minutes. Thesolid was collected as A557 (5 mg, 56%). HPLC: 93%, retention time:1.580 minute (condition A). Chiral HPLC: 88.2% ee. retention time: 12.05minute (Chiralpak AD 10 um 4.6×250 mm; Hex/MeOH/IPA/DEA=60/20/20/0.1;1.8 ml/min). LC/MS (M+H)⁺=337. ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.15 (1H,s), 7.82 (1H, s), 7.73 (1H, d, J=7.63 Hz), 7.45 (1H, t, J=7.88 Hz), 7.30(1H, d, J=7.63 Hz), 7.15 (1H, s), 4.33 (1H, dd, J=7.88, 4.32 Hz), 4.07(3H, s), 3.83-3.89 (1H, m), 3.74-3.81 (1H, m), 3.16 (3H, s).

Example A558(R)-N-(2-hydroxy-1-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethyl)acetamide

A solution of A557 (4.5 mg, 0.0134 mmol) and triethylamine (6.5 uL,0.0468 mmol) in dichloromethane (0.5 mL) at 0-5° C. was added acetylchloride (0.99 uL, 0.014 mmol) and the reaction mixture was stirred at0-5° C. for 10 minutes, which was warmed up to room temperature andstirred for 10 minutes. The reaction mixture was concentrated andpurified on prep. HPLC (condition G) to yield A558 (1.6 mg, 32%).HPLC: >95%, retention time: 1.712 minute (condition A). LC/MS(M+H)⁺=379, ¹H-NMR (400 MHz, CD₃OD) δ ppm 7.76 (1H, s), 7.61 (1H, s),7.54 (1H, d, J=7.63 Hz), 7.26 (1H, t, J=7.88 Hz), 7.08 (1H, d, J=8.14Hz), 6.91 (1H, s), 4.93 (1H, dd, J=7.38, 5.34 Hz), 3.98 (3H, s),3.63-3.75 (2H, m), 3.01 (3H, s), 1.94 (3H, s).

Example A559(R)-N-(2-hydroxy-1-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethyl)-2-methoxyacetamide

A559 was prepared in a similar manner to A558. HPLC: 90%, retentiontime: 1.963 minute (condition A). LC/MS (M+H)⁺=409. ¹H NMR (500 MHz,CD₃OD) δ ppm 8.16-8.22 (1H, m), 7.72-7.75 (1H, m), 7.65-7.69 (1H, m),7.42-7.47 (1H, m), 7.30-7.35 (1H, m), 7.16-7.19 (1H, s), 5.07-5.12 (1H,m), 4.15 (3H, s), 3.95-3.98 (2H, m), 3.84-3.88 (2H, m), 3.46 (3H, s),3.26 (3H, s).

A560(S)-2-amino-2-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethanol

A560.1:(S)-2-tert-butyloxycarbonylamino-2-(3-(1-methyl-4-(N-methyl-tert-butyloxycarbonylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethanol

A solution of tert-butyl carbamate (17.6 mg, 0.15 mmol) in n-propanol(0.2 ml) was added 1N NaOH solution (0.15 ml, 0.15 mmol), water (0.15ml), followed by t-BuOCl (17 uL, 0.15 mmol) and stirred at RT for 20minutes. The reaction mixture was cooled to 0-5° C. (DHQD)₂PHAL (1.95mg, 0.0025 mmol) in n-propanol (0.16 ml) was added and then A553.3 (20mg, 0.05 mmol) in n-propanol (0.4 ml) was added. Finally, to thereaction mixture was added K₂OsO₄o2H₂O (0.74 mg, 0.002 mmol) at 0-5° C.The color of solution was changed from faint yellow to green and then toyellow. The reaction mixture was stirred for 2 hrs from at 0° C. to atRT and the reaction was quenched with saturated NaHSO₃ solution (1 mL)and stirred for 15 minutes which was extracted with EtOAC (1 ml×3). Thecombined organic phases was washed with water (1 ml), brine (1 ml) andthe organic layer was dried over sodium sulfate. Filtration andconcentration to yield a crude product. It was purified on prep. silicagel TLC plate with EtOAc/MeOH (10/1) to yield as A560.1 (13.4 mg, 50%).HPLC: 89%, retention time: 3.051 minute (condition A). LC/MS (M+H)⁺=537.

A560.2:(S)-2-amino-2-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethanol

A suspension solution of A560.1 (13.4 mg, 0.025 mmol) in CH₂Cl₂ (1 ml)at 0-5° C. was added 4N HCl in dioxane (0.4 ml, 1.6 mmol) dropwise. Thereaction mixture was warmed up to RT and stirred for 20 minute which wasconcentrated to yield a crude product. It was purified on prep. silicagel TLC plate with CH₂Cl₂/MeOH/NH₄OH (90/15/1.5) to yield A560 (5.2 mg,62%). HPLC: 91%, retention time: 1.582 minute (condition A). ChiralHPLC: 88.8% ee. retention time: 15.69 minute (Chiralpak AD 10 um 4.6×250mm; Hex/MeOH/IPA/DEA=60/20/20/0.1; 1.8 ml/min). LC/MS (M+H)⁺=337. ¹H-NMR(400 MHz, CD₃OD) δ ppm 7.90 (1H, s), 7.80 (1H, s), 7.71 (1H, d, J=8.14Hz), 7.42 (1H, t, J=7.63 Hz), 7.25 (1H, d, J=7.63 Hz), 7.07 (1H, s),4.07-4.16 (4H, m), 3.78-3.88 (1H, m), 3.64-3.75 (1H, m), 3.15 (3H, s)

Example A5611-(1-(3-(1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl)ethyl)pyrrolidin-2-one

To a solution A131 (8 mg, 0.02 mmol) in THF (5 mL) was added DIPEA(0.018 mL) followed by 4-chlorobutanoyl chloride (0.0072 mL, 0.06 mmol).The reaction was stirred at room temperature for 30 minutes thenpartitioned between EtOAc and saturated aq. NaHCO₃. The EtOAc layer waswashed with water and brine then dried over MgSO₄, filtered, andevaporated to dryness. The residue thus obtained was dissolved in THF (5mL), cooled with an ice bath, and excess sodium hydride (95%) was added.The reaction was warmed to room temperature overnight, then heated togentle reflux. An additional portion of sodium hydride was added. After3 hours at reflux, KOtBu (solid, excess amount) was added and heatingcontinued for 48 hours. The material was then placed in a sealed tubealong with fresh KOtBu and heated to 85° C. overnight. The reaction wasquenched with water, extracted with EtOAc and the crude organics wereconcentrated and further purified by preparative reverse phase HPLC toafford the desired product (0.92 mg, 1×TFA) as a clear film. Thecompound had an HPLC retention time=2.7 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.2% H₃PO₄;Solvent B=90% MeOH, 10% H₂O, and 0.2% H₃PO₄) and a LC/MS M⁺¹=389.4

Example A5627-isopropyl-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A562.1: tert-butyl7-iodo-1-methyl-6-(2,2,2-trifluoroacetamido)-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

To a solution of A1.12 (100 mg, 0.248 mmol) in THF (5 mL) andtriethylamine (0.038 mL) at room temperature was added trifluoroaceticanhydride (0.070 mL, 0.496 mmol) dropwise. The reaction was stirred atroom temperature overnight then diluted with EtOAc (15 mL) and washedwith saturated aq. NaHCO₃ (10 mL). The EtOAc layer was washed with water(10 mL) and brine (10 mL) then dried over MgSO₄, filtered, andevaporated to dryness to afford A562.1 as a yellow solid (118 mg). Thecompound had an HPLC retention time=2.76 min. (Column: ChromolithSpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and 0.2% H₃PO₄;Solvent B=90% MeOH, 10% H₂O, and 0.2% H₃PO₄) and a LC/MS M^(+Na)=522.01

A562.2: tert-butyl7-isopropyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of A562.1 (20 mg, 0.04 mmol), 3-methylbut-1-yne (0.006 mL),polymer supported triphenylphosphine (3 mmol/g, 12 mg), CuI (2.3 mg,0.012 mmol), and potassium carbonate (11.1 mg, 0.08 mmol) in DMF (0.6mL) was heated in a Personal Chemistry microwave reactor for 1 hour at160° C. followed by an additional processing time of 30 minutes at 160°C. The material was filtered through a glass frit, which was washed withmethanol, and purified by preparative reverse phase HPLC to affordA562.2 (4.3 mg, 1×TFA). The compound had an HPLC retention time=2.68min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH,90% H₂O, and 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, and 0.2% H₃PO₄)and a LC/MS M⁺¹=344.2

A562:7-isopropyl-N,1-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

To a solution of A562.2 (4 mg, 1×TFA) in methanol (1 mL) was addedHCl/Dioxane (4N, 2 mL). The reaction was stirred at room temperatureuntil complete as judged by HPLC analysis, then evaporated and driedunder high vacuum to afford the A562 as an off-white solid (2.5 mg,1×HCl). The compound had an HPLC retention time=2.22 min. (Column:Chromolith SpeedROD 4.6×50 mm—4 min.; Solvent A=10% MeOH, 90% H₂O, and0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, and 0.2% H₃PO₄) and a LC/MSM⁺¹=244.2

Examples A563-A565 described in Table A72 were prepared in a similarmanner to Example A562. TABLE A27

HPLC Reten- MS tion Re- Ex. R Name (min) ported A563

7-cyclohexyl-N,1-dimethyl- 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 2.90 284.2 A564

N,1-dimethyl-7-(pyridin-4- yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 1.36 279.2 A565

N,1-dimethyl-7-(1-methyl- 1H-imidazol-5-yl)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4- amine 0.69 282.3

Example B1 1,6-dihydro-1-methyl-7-phenylimidazo[4,5-d]pyrrolo[2,3-b]pyridine

B1.1: 4-chloro-5-nitropyridin-2-amine

Commercially available 3-nitro-4-chloropyridine (25 g, 157 mmol) wasdissolved in liquid ammonia (1.4 L) and KMnO₄ (50 g, 316 mmol) was addedand the mixture stirred for 5 h. at liq ammonia temperature. Thereaction mixture was brought to RT and ammonia was allowed to evaporate.Water (1.5 L) was added and the mixture extracted with chloroform (10×2L) for 20 h. The organic layer was washed with water, brine, separated,dried over sodium sulphate and concentrated under reduced pressure. Theproduct was purified by 60-120 silica gel column chromatography usingchloroform as eluent to give 11.2 g (40%) B1.1 as a yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ 8.80 (s, 1H), 7.64 (s, 1H), 6.58 (s, 1H). LCMS(M−H)⁺=173.

B1.2: tert-Butyl 4-chloro-5-nitropyridin-2-ylcarbamate

B1.1 (10 g, 57.6 mmol) was dissolved in dry acetonitrile (750 mL) andDMAP (1.41 g, 12 mmol) was added. The reaction mixture was cooled at 0°C. and di-tert-butyldicarbonate (16.34 g, 75 mmol) was added drop-wiseby addition funnel for 30 min. The reaction mixture was warmed to RT andstirred for overnight. The reaction mixture was concentrated and theresidue was dissolved in ethyl acetate. The organic was layer washedwith water and brine solution, separated, dried over sodium sulphate andconcentrated. The product was purified by column chromatography using 5%of ethyl acetate in pet ether to give 9 g (57%) of B1.2 as a yellow. ¹HNMR (300 MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.03 (s, 1H), 8.09 (s, 1H) 1.49(s, 9H). LCMS (M−H)⁺=272.

B1.3: tert-Butyl 4-(methylamino)-5-nitropyridin-2-ylcarbamate

B1.2 (9 g, 32.88 mmol) was dissolved in dry THF (50 ml) in an autoclave.Methyl amine solution (20% in THF, 2.59 g, 82 mmol) was added and thereaction mixture was heated at 80° C. for 3 h. The reaction mixture wasconcentrated under reduced pressure and methanol was added to theresidue and cooled to 0° C. The solid was collected by filtration. Thefiltered cake was washed with cold MeOH to give 8 g (91%) of B1.3 as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.16 (s, 1H), 8.84 (s, 1H),8.44 (bs, 1H) 7.27 (s, 1H), 2.92 (d, 3H), 1.47 (s, 9H). LCMS (M−H)⁺=269.

B1.4: tert-Butyl 5-amino-4-(methylamino)pyridin-2-ylcarbamate

B1.3 (8 g, 30 mmol) was dissolved in methanol (1000 ml). Pd/C (1 g) wasadded cautiously and the mixture hydrogenated at 2 kg pressure for 12 husing a Parr shaker. The reaction mixture was filtered over Celite andconcentrated to provide the crude product. The solid was washed withpetrolium ether to give 6.55 g (92%) of B1.4 as a black solid. ¹H NMR(300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 7.33 (s, 1H), 6.83 (s, 1H) 5.59 (s,1H), 4.25 (bs, 2H), 2.74 (d, 3H), 1.44 (s, 9H). LCMS (M−H)+239.

B1.5: tert-butyl 1-methyl-1H-imidazo[4,5-c]pyridin-6-ylcarbamate

B1.4 (0.5 g, 2.1 mmol) was dissolved in diethoxymethyl acetate (5 ml)and stirred at room temperature for 16 h. Reaction mixture was pouredinto water (150 ml) and extracted with ethyl acetate (2×100 ml). Thecombined organic layers were washed with water, with brine, dried oversodium sulphate and concentrated to provide the crude product which wastriturated with pet ether and filtered to yield 0.350 g (62%) of B1.5 asa brown solid. ¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 8.59 (s, 1H),8.19 (s, 1H) 7.91 (s, 1H), 3.79 (s, 3H), 1.48 (s, 9H). LCMS (M−H)⁺=249.

B1.6: 1-methyl-1H-imidazo[4,5-c]pyridin-6-amine hydrochloride salt

B1.5 (0.3 mg, 1.2 mmol) was taken in HCl in THF (10 ml, 4N solution) andstirred at room temperature overnight. The solvent was removed underreduced pressure and the solid obtained was washed with ethyl acetateand dried to provide B1.6, 200 mg (90%) as the hydrochloride salt. ¹HNMR (300 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.41 (s, 1H), 7.31 (bs, 2H) 6.83(s, 1H), 3.74 (s, 3H). LCMS (M−H)⁺=149.

B1.7: 7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-6-amine

B1.6 (75 mg, 0.4 mmol) was dissolved in methanol (2.5 ml) and sodiumacetate (66 mg, 0.8 mmol) was added. The reaction mixture was cooled to0° C. and N-iodosuccinimide (100 mg, 0.44 mmol) was added in portions.The reaction mixture was stirred at room temperature for 3 h. Reactionmixture was concentrated to remove volatiles and the residue waspurified by column chromatography over silica gel (60-120) usingchloroform-methanol (95:5) as eluent to provide 70 mg (63%) of B1.7 as ayellow solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.28 (s, 1H), 7.98 (s, 1H),5.75 (s, 2H) 4.02 (s, 3H). LCMS (M−H)⁺=275.

B1.8: 1-methyl-7-(2-phenylethynyl)-1H-imidazo[4,5-c]pyridin-6-amine

B1.7, (0.1 g, 0.364 mmol), bis(triphenylphosphine)palladium(II)chloride(0.012 g, 0.018 mmol), and triethylamine (0.5 mL) were dissolved in dryDMF (4 mL) and phenylacetylene (0.074 g, 0.73 mmol) was added. Thereaction mixture was heated to 75° C. for 2 h. The reaction mixture wascooled to rt and poured into water and extracted with ethyl acetate(2×30 mL), washed with water and brine solution and the organic layerseparated and evaporated under reduced pressure. The residue waspurified by column chromatography using 5% of ethyl acetate in pet etherto provide 65 mg (72%) of B1.8. ¹H NMR (400 MHz, CD₃OD) δ 8.36 (s, 1H),7.99 (s, 1H), 7.64-7.62 (m, 2H) 7.44-7.42 (m, 3H), 4.17 (s, 1H). LCMS(M−H)⁺=249.

B1.9: 1,6-dihydro-1-methyl-7-phenyl imidazo[4,5-d]pyrrolo[2,3-b]pyridine

B1.8 (40 mg, 0.16 mmol) was dissolved in N,N-dimethylacetamide (1 mL)and potassium tert-butoxide (40 mg, 0.36 mmol) was added. The reactionmixture was irradiated in a microwave reactor at 100° C. for 30 min. Thereaction mixture was cooled to rt and poured into water and extractedwith ethyl acetate (2×15 mL), washed with water and brine solution, theorganic layer separated and concentrated under reduced pressure. Thecrude product was purified by crystallization from ethyl acetate toprovide 22 mg (55%) of B1 as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.75 (s, 1H), 8.14 (s, 1H), 7.92 (d, 2H) 7.50-7.47 (t, 2H), 7.38-7.34(m, 1H), 7.26 (s, 1H), 4.21 (s, 3H). LCMS (M−H)⁺=249.

Example B23-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-benzonitrile

B2.1:3-(6-Amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-ylethynyl)-benzonitrile

A mixture of compound A1.7 (1 g, 3.65 mmol), 3-ethynyl-benzonitrile(0.93 g, 7.3 mmol), bis(triphenylphosphine)palladium(II)chloride, (0.13g, 0.18 mmol) and triethylamine (10 ml) were taken in DMF (20) ml andstirred at 85° C. for 6 h. The reaction mixture was cooled to rt,solvent was removed under reduced pressure and the crude product wasrecrystallised from ethylacetate to get 0.66 g (66%) of B1.1 as brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.39 (s, 1H), 8.25 (s, 1H), 7.98-8.00(m, 2H), 7.83-7.85 (d, 1H), 7.60-7.63 (t, 1H), 6.36 (bs 2H) 4.03 (s,3H). LCMS (M−H)⁺=274

B2.2:3-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

0.66 g (2.4 mmol) of B2.1 was taken in N,N-dimethylacetamide (15 ml) andadded 0.6 g (5.4 mmol) of potassium tert-butoxide. The reaction mixturewas irradiated in MW reactor at 110° C. for 30 min. Reaction mixture wascooled to rt and poured into water and extracted with ethyl acetate(3×250 ml), washed with water and brine solution. The product waspurified by crystallization from ethyl acetate to give 350 mg (58%) ofB2 as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.47 (s,1H), 8.29-8.31 (d, 1H), 8.16 (s, 1H), 7.74-7.76 (d, 1H), 7.64-7.69 (t,1H), 7.61 (s, 1H), 4.11 (s, 3H). LCMS (M−H)⁺=274

Example B33-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-benzenemethanamine

325 mg (1.12 mmol) compound B2 was hydrogenated using Raney nickel (300mg) in methanol (30 ml) and aq NH₃ (6 ml) at 5 kg pressure for 48 hours.(HPLC analysis shows the presence of starting material. Reaction mixturewas filtered over Celite, filtrate was concentrated and the crude wasonce again taken for hydrogenation using 300 mg of Raney nickel in 30 mlmethanol and aq NH₃ (6 ml) at 5 kg pressure for 48 h. Reaction mixturewas filtered over Celite and the filtrate was concentrated. Crudematerial was recrystallised from ethylacetate to get 200 mg of theproduct, B3 as brown solid (61%). ¹H NMR (400 MHz, CD₃OD) δ: 8.60 (s,1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.86-7.88 (d, 1H), 7.52-7.54 (t, 1H),7.41 (d, 1H), 7.32 (s, 1H), 4.24 (s, 3H), 4.0 (s, 2H). LCMS (M−H)⁺=278.

Example B4N-[1-[3-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]ethyl]-acetamide

B4.1:N-(1-(3-((6-Amino-1-methyl-1H-imidazo[4,5-c]pyridin-7-yl)ethynyl)phenyl)ethylacetamide

A solution of B 1.7 (0.20 g, 0.73 mmol),dichlorobis(triphenylphosphine)palladium II (30.74 mg, 0.044 mmol), andtriethylamine (2.94 mL, 21.2 mmol) in DMF (2.0 mL) was degassed forseveral minutes with argon. A56.1b (0.137 g, 0.73 mmol) was added over 7minutes in small increments while heating at 90° C. under Ar. Aftercompletion of the addition, heating at 90° C. was continued for 1 h. Asecond portion of A56.1b (70.0 mg (0.37 mmol) was added in smallportions, and heating at 90° C. was continued for 1 h. The reactionmixture was evaporated to dryness under vacuum. Flash chroma-tography onsilica gel, eluting with an EtOAc:hexane gradient followed by anEtOAc:MeOH:ammonium hydroxide gradient and an ether trituration yielded0.2113 g of B4.1 as a yellow solid (86.6%). HPLC (C): 86.05%, ret. time1.83 min., LC/MS (M+H)⁺=373.36.

B4.2:N-[1-[3-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]ethyl]-acetamide

A solution of B4.1 (0.155 g, 0.46 mmol) and potassium tert-butoxide(0.58 mL, 1.0M solution in THF, 0.58 mmol) in 2.61 mL of DMA was heatedat 90° C. under Ar for 40 min. After removal of the DMA, the crudeproduct was purified by reversed-phase preparative HPLC to yield 109.8mg of B4 as a pale yellow solid (53% assuming 1.0 TFA salt). HPLC (C):98.14%, ret. time 1.87 min., LC/MS (M+H)⁺=334.33.

Example B53-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-alpha-methyl-benzenemethanamine

A solution of B4 (103.1 mg, 0.23 mmol) in EtOH (3.0 mL) and con. HCl(3.0 mL) was heated in a sealed pressure tube at 150° C. for 4 hours and15 minutes. The reaction mixture was evaporated to dryness under vacuumwith toluene to yield B5 as a yellow solid (75.7 mg, 100%). HPLC (C):97.0%, ret. time 1.50 min., LC/MS (M+H)⁺=292.45.

Example B6N-[1-[3-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]ethyl]-3-methoxy-propanamide

Diisopropylethylamine (26.1 μL, 0.153 mmol) was added to a solution ofB4 (10.0 mg, 0.0305 mmol), EDC (11.70 mg, 0.061 mmol),1-Hydroxybenzotriazole hydrate (5.60 mg, 0.037 mmol), and3-methoxypropionic acid (3.76 μL, 0.040 mmol) in DMF (0.70 mL). Thereaction mixture was heated at 60° C. for 1 hand 10 min. in sealed vialson a platform shaker. After solvent removal, the crude product waspurified by reversed-phase preparative HPLC to yield 11.60 mg of B6 as apale yellow solid (68% assuming 1.0 mol TFA). HPLC (C): 95%, ret. time1.97 min., LC/MS (M+H)⁺=378.47.

Examples B7-B11

Examples B7-B11 were prepared in a manner similar to that used forexample B6. TABLE B1

HPLC Reten- MS tion Re- Ex. R Name (min) ported B7

N-[1-[3-(1,6-dihydro-1- methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]ethyl]-1-hydroxy- cyclopropanecarboxamide 1.96 376.47 B8

N-[1-[3-(1,6-dihydro-1- methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]ethyl]-2-hydroxy- acetamide 1.82 350.42 B9

2-(acetylamino)-N-[1- [3-(1,6-dihydro-1- methylimidazo[4,5-d]pyrrolo[2,3 -b]pyridin-7- yl)phenyl]ethyl]-acetamide 1.81 391.46 B10

N-[1-[3-(1,6-dihydro-1- methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]ethyl]- 2-methoxy-acetamide 1.99 364.44

Example B11N-[[3-(1,6-dihydro-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]methyl]-acetamide

Diisopropylethylamine (24.7 μL, 0.184 mmol) was added to a solution ofB3 (10.0 mg, 0.036 mmol), EDC (13.82 mg, 0.072 mmol),1-Hydroxybenzotriazole hydrate (6.63 mg, 0.043 mmol), and acetic acid(2.68 μL, 0.046 mmol) in DMF (0.72 mL). The reaction mixture was heatedat 60° C. for 50.0 min. in sealed vials on a platform shaker. Aftersolvent removal, the crude product was purified by reversed-phasepreparative HPLC to yield 9.3 mg of B11 as a tan solid (60% assuming 1.0mol TFA). HPLC (C): 91.1%, ret. time 1.73 min., LC/MS (M+H)⁺=320.36.

Examples B12-B16

Examples B12-B16 were prepared in a manner similar to that used forexample B11. TABLE B2

HPLC Reten- MS tion Re- Ex. R Name (min) ported B12

N-[[3-(1,6-dihydro-1- methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]methyl]-3- methoxy-propanamide 1.73 364.39 B13

N-[[3-(1,6-dihydro-1- methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]methyl]-2- pyridinecarboxamide 2.22 383.37 B14

N-[[3-(1,6-dihydro-1- methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]methyl]-2- (methylsulfonyl)-benzamide 2.00 460.33 B15

2-cyano-N-[[3- (1,6-dihydro- 1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)phenyl]methyl]- acetamide 1.67 345.38 B16

N-[[3-(1,6-dihydro-1- methylimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)phenyl]methyl]- 2-methyl- propanamide 1.92 348.42

HPLC conditions used to determine retention times; LCMS conditions=B: 4min gradient 0-100% B in A (A; 0.1% TFA in 90/10 water/methanol; B; 0.1%TFA in 10/90 water/methanol) using a Waters Sunfire C18 (4.6×50 mm)column at with a detection wavelength of 220 nanometers.

Example C13-(1,6-dimethyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

C1.1: 3-fluoro-5-((trimethylsilyl)ethynyl)benzonitrile

To a solution of commercially available 3-bromo-5-fluorobenzonitrile (5g, 25 mmol) and triethylamine (35 ml) in 35 ml of THF was bubblednitrogen for 10 min. Then added trimethylsilylacetylene (5.0 g, 50mmol), copper iodide (60 mg, 0.31 mmol), and PdCl₂(PPh₃)₂ (80 mg, 0.11mmol) and the reaction mixture was heated with a heating mantle. Afteran initial exotherm, the reaction was heated at reflux for 3 hrs. Thereaction mixture was concentrated on a rotary evaporator and the darkresidue diluted with hexane and washed with water three times. Thehexane layer was filtered through Celite and the filtrate wasconcentrated to give a brown oil. The crude material was used withoutfurther purification. LCMS B: Ret time 3.96 min, (M+H)⁺=218.14. ¹H NMR,400 MHz, CDCl₃: 7.57 (s, 1H), 7.43 (m, 1H), 7.35 (m, 1H), 0.26 (s, 9H).

C1.2: 3-ethynyl-5-fluorobenzonitrile

To a solution of 5.4 g (0.025 mol) of C1.1 in 40 ml of THF was added a 1mL solution of 30% potassium hydroxide in water. The reaction mixturewas stirred at RT for 1 hr. The reaction mixture was concentrated on arotary evaporator and the dark residue diluted with ethyl acetate. Theextract was washed with water, brine and concentrated. The product waspurified on silica gel column using 5% of ethyl acetate in hexane togive 2.5 g (69%) of C1.2 as a white solid. LCMS B: Ret time 2.63 min,(M+H)⁺=145.98. ¹H NMR, 400 MHz, CDCl₃: 7.57 (s, 1H), 7.42 (dm, 1H), 7.35(dm, 1H), 3.25 (s, 1H).

C1.3: tert-butyl6-amino-7-((3-cyano-5-fluorophenyl)ethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A1.12tert-Butyl-6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate(3.2 g, 7.9 mmol), dichlorobis(triphenylphosphine)palladium (270 mg,0.38 mmol), 3-ethynyl-5-fluorobenzonitrile (C1.2) (1.5 g, 10 mmol), CuI(75 mg, 0.39 mmol), diisopropylamine (15 mL) were added toN,N-dimethylformamide (15 mL). The reaction mixture was heated at 90° C.(in preheated oil bath) for 60 min. Additional3-ethynyl-5-fluorobenzonitrile (C1.2) (0.5 g, 3.4 mmol) was added to thereaction mixture and heated for another 60 min. The reaction was cooledand diluted with ethyl acetate and washed several times with water. Thesolvent removed under reduced pressure and the residue was purified bysilica gel column chromatography (50%-70% ethyl acetate/hexane) to give3.0 g (90%) of C1.3. LCMS B: Ret time 2.98 min, (M+H)=421.31, ¹H NMR,400 MHz, CDCl₃: 7.62 (s, 1H), 7.57 (s, 1H), 7.42 (dm, 1H), 7.35 (dm,1H), 5.00 (bs, 2H), 4.05 (s, 3H), 3.39 (s, 3H), 1.44 (s, 9H).

C1.4: tert-butyl7-((3-cyano-5-fluorophenyl)ethynyl)-1-methyl-6-(2,2,2-trifluoroacetamido)-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A solution of C1.3 (2.9 g, 6.9 mmol) and triethylamine (1.4 g, 14 mmol)in methylene chloride was cooled in an ice bath and treated dropwisewith a solution of trifluoroacetic acid anhydride (2.9 g, 13.8 mmol) in4 ml of methylene chloride. The reaction was stirred at 0° C. for 1 hr.The mixture was washed with water, sat'd NaHCO₃, and brine. Dried overNa₂SO₄, filtered and concentrated to give 3.5 g of C1.4 as tan solid.LCMS B: Ret time 3.38 min, (M+H−Boc)⁺=417.18.

C1.5: tert-butyl7-(3-cyano-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C1.4 (1.7 g, 3.3 mmol) in dimethylacetamide (18 mL) wastreated with K₂CO₃ (0.63 g, 4.6 mmol) anddichlorobis(triphenylphosphine)palladium (55 mg, 0.08 mmol) and heatedat 110° C. in an oil bath for 8 hrs. The reaction was cooled, dilutedwith ethyl acetate and washed several times with water. The solventremoved under reduced pressure and the residue titurated with methanol.The solid was filtered and rinsed with CH₂Cl₂/Hexane mixture to give0.77 g of C1.5 as tan solid. The combined filtrates were concentratedand the residue was chromatographed on silica gel using ethyl acetate asthe eluent to give an additional 200 mg of C1.5. LCMS B: Ret time 2.97min, (M+H)⁺=421.26, (M+H−Boc)⁺=321.26.

C1.6: tert-butyl7-(3-cyano-5-fluorophenyl)-1,6-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C1.5 (35 mg, 0.08 mmol) in DMF (2 ml) was cooled in an icebath and treated with a 1 M solution of NaN(TMS)₂ (0.2 ml, 0.2 mmol) inTHF and then with MeI (28 mg, 0.19 mmol). The mixture was stirred at 0°C. for 30 min and then at room temperature for 1 hour. The mixture wasdiluted with water and extracted into ethyl acetate. The organic extractwas washed with water several times and concentrated to give C1.6 as atan solid. LCMS B: Ret time 2.99 min, (M+H)⁺=435.26, (M+H−Boc)⁺=335.28.¹H NMR, 400 MHz, CDCl₃: 7.82 (s, 1H), 7.68 (s, 1H), 7.52 (dm, 1H), 7.41(dm, 1H), 6.84 (s, 1H), 4.10 (s, 3H), 3.97 (s, 3H), 3.51 (s, 3H), 1.44(s, 9H).

C1:3-(1,6-dimethyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

A solution of C1.6 (36 mg, 0.08 mmol) in CH₂Cl₂ (2 ml) was treated with6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuechromatographed on silica gel eluting with 8% NH₄OH/MeOH/CH₂Cl₂(0.8:7.2:92) to give 20 mg of C1 as yellow solid. LCMS B: Ret time 2.65min, (M+H)⁺=335.27. ¹H NMR, 400 MHz, CDCl₃: 7.63 (s, 1H), 7.62 (s, 1H),7.47 (dm, 1H), 7.27 (dm, 1H), 6.70 (s, 1H), 5.50 (bs, 1H), 4.03 (s, 3H),3.92 (s, 3H), 3.23 (d, J=5 Hz, 3H).

Example C23-[1,6-dihydro-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl]-5-fluoro-benzonitrile

A solution of C1.5 (25 mg, 0.06 mmol) in CH₂Cl₂ (0.25 ml) was added TFA(0.25 ml) dropwise at 0-5° C. which was warmed up to RT and stirred for20 minutes. The reaction mixture was concentrated and purified on prep.HPLC (condition G) to yield C2 (7.5 mg, 23%). HPLC: >95%, retentiontime: 2.382 minute LC/MS (M+H)⁺=321, ¹H-NMR (400 MHz, DMSO-d₆) δ ppm8.18 (1H, s), 8.14 (1H, s), 8.01 (1H, d, J=10.17 Hz), 7.56 (1H, d,J=7.63 Hz), 7.52 (1H, s), 4.04 (3H, s), 2.99 (3H, s).

Example C33-(6-allyl-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitriletrifluoacetate salt

C3.1: tert-butyl6-allyl-7-(3-cyano-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C1.5 (42 mg, 0.10 mmol) in DMF (3 ml) was cooled in an icebath and treated with a 1 M solution of NaN(TMS)₂ (0.2 ml, 0.2 mmol) inTHF and then with allyl iodide (33 mg, 0.20 mmol). The mixture wasstirred at 0° C. for 30 min and then at room temperature for 1 hour. Themixture was diluted with water and extracted into ethyl acetate. Theorganic extract was washed with water several times and concentrated togive C3.1 as a tan solid. LCMS B: Ret time 3.20 min, (M+H)⁺=461.26,(M+H−Boc)⁺=361.26.

Alternate Preparation of C3.1

A solution of C2 (95 mg, 0.226 mmol) in DMF at 0-5° C. was added NaHMDS(0.407 ml, 0.407 mmol) and the reaction mixture was stirred at 0-5° C.for 10 minutes. Allyl bromide was added at 0-5° C. dropwise. Thereaction mixture was warmed up to room temperature and stirred for 30minutes. The reaction mixture was concentrated and then it was addedwater (2 ml) and stirred for 5 minutes. The solid was collected as C3.1(100 mg, 96%). HPLC: 78%, retention time: 3.178 minute (condition B).LC/MS (M+H)⁺=461, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.03 (1H, s), 7.78 (1H,s), 7.66 (1H, d, J=9.66 Hz), 7.53 (1H, d, J=8.14 Hz), 7.08 (1H, s),5.83-6.00 (1H, m), 4.93-5.04 (2H, m), 4.58 (1H, d, J=17.29 Hz),4.02-4.12 (4H, m), 3.27 (3H, s), 1.19-1.34 (9H, m).

Alternate Preparation of C3.1

A solution of C1.5 (500 mg, 1.19 mmol) in DMF (8 ml) was treated withCs₂CO₃ (900 mg, 2.8 mmol) and allyl bromide (500 mg, 4.1 mmol) andstirred at room temperature overnight. The mixture was diluted withethyl acetate (150 ml) and washed several times with water. The solutionwas concentrated on a rotary evaporator and the residue chromatographedon silica gel eluting with 2%-3% NH₄OH/MeOH/CH₂Cl₂(0.2:1.8:98-0.3:2.7:97) to give C3.1 as a light yellow solid. LCMS B:Ret time 3.23 min, (M+H)⁺=461.27. ¹H NMR, 400 MHz, CDCl₃: 7.87 (s, 1H),7.71 (s, 1H), 7.57 (dm, 1H), 7.39 (dm, 1H), 6.86 (s, 1H), 6.04 (m, 1H),5.16 (m, 1H), 5.03 (m, 2H), 4.83 (m, 1H), 4.11 (s, 3H), 3.48 (s, 3H),1.43 (s, 9H).

Also obtained was obtained from the column 100 mg of tert-butyl8-allyl-7-(3-cyano-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamateC3.1a as an orange solid. LCMS B: Ret time 2.61 min, (M+H)⁺=461.36

C3:3-(6-allyl-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitriletrifluoacetate salt

A solution of C2.1 (36 mg, 0.08 mmol) in CH₂Cl₂ (2 ml) was treated with6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas purified by preparative HPLC and lyophilized to give 5 mg of C3 asyellow solid. LCMS B: Ret time 2.93 min, (M+H)⁺=361.33.

Example C4 methyl2-(7-(3-cyano-5-fluorophenyl)-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)acetate

C4.1 methyl2-(4-(tert-butoxycarbonyl(methyl)amino)-7-(3-cyano-5-fluorophenyl)-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)acetate

A solution of C1.5 (200 mg, 0.47 mmol) in DMF (2 ml) was cooled in anice bath and treated with a 1 M solution of NaN(TMS)₂ (1.0 ml, 1.0 mmol)in THF and then with methyl bromoacetate (250 mg, 1.6 mmol). The mixturewas stirred at 0° C. for 30 min and then at room temperature for 1 hour.The mixture was diluted with water and extracted into ethyl acetate. Theorganic extract was washed with water several times and concentrated andthe residue chromatographed on silica gel eluting with ethyl acetate togive 170 mg of C4.1 as a tan solid. LCMS B: Ret time 2.85 min,(M+H)⁺=493.26, ¹H NMR, 400 MHz, CDCl₃: 7.82 (s, 1H), 7.68 (m, 1H), 7.63(s, 1H), 7.48 (m, 1H), 6.87 (s, 1H), 5.11 (s, 2H), 4.10 (s, 3H), 3.75(s, 3H), 3.46 (s, 3H), 1.42 (s, 9H).

C4: methyl2-(7-(3-cyano-5-fluorophenyl)-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)acetate

A solution of C4.1 (20 mg, 0.04 mmol) in CH₂Cl₂ (2 ml) was treated with6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuechromatographed on silica gel eluting with 10% NH₄OH/MeOH/CH₂Cl₂(1:9:90) to give 10 mg of C4 as yellow solid. LCMS B: Ret time 2.61 min,(M+H)⁺=393.19. ¹H NMR, 400 MHz, CDCl₃: 7.67 (s, 1H), 7.62 (s, 1H), 7.47(m, 1H), 7.27 (m, 1H), 6.72 (s, 1H), 5.53 (bs, 1H), 5.05 (s, 2H), 4.01(s, 3H), 3.76 (s, 3H), 3.15 (d, J=5 Hz, 3H).

Example C52-(7-(3-cyano-5-fluorophenyl)-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)acetamidetrifluoacetate salt

C5.1:2-(4-(tert-butoxycarbonyl(methyl)amino)-7-(3-cyano-5-fluorophenyl)-1-methylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)aceticacid

A solution of C4.1 (150 mg, 0.3 mmol) in MeOH/THF (3 ml/3 ml) wastreated with 3 ml of 1N NaOH and stirred at RT for 5 hours. Made acidicwith 4 ml 1N HCl and extracted into ethyl acetate. Concentrated to give100 mg of C5.1 as a solid. LCMS B: Ret time 2.67 min, (M+H)⁺=479.20.

C5.2: tert-butyl6-(2-amino-2-oxoethyl)-7-(3-cyano-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C5.1 (50 mg, 0.10 mmol) in THF/DMF (3 ml/l ml) was treatedwith EDC (24 mg, 0.12 mmol), HOBT (18 mg, 0.12 mmol), Et₃N (12 mg, 0.12mmol) and 3 ml of a 0.5 M NH₃ (in dioxane) at RT and stirred overnight.The solvent was removed under vacuum and the residue dissolved in CH₂Cl₂and washed with water. The CH₂Cl₂ was removed on a rotary evaporator andthe residue chromatographed on silica gel eluting with 8%NH₄OH/MeOH/CH₂Cl₂ to give 20 mg of C5.2. LCMS B: Ret time 2.33 min,(M+H)⁺=478.22.

C5:2-(7-(3-cyano-5-fluorophenyl)-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)acetamidetrifluoacetate salt

A solution of C5.2 (20 mg, 0.04 mmol) in CH₂Cl₂ (2 ml) was treated with6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas purified by preparative HPLC and lyophilized to give 4 mg of C5 asyellow solid. LCMS B: Ret time 2.05 min, (M+H)⁺=378.20.

Example C63-(6-ethyl-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained starting with intermediate C1.5 (20 mg, 0.048 mmol)and ethyl iodide (36 mg, 0.22 mmol) and using the procedure describedfor the synthesis of Example C1. Obtained 6 mg of C6 as a yellow solid.LCMS B: Ret time 2.93 min, (M+H)⁺=349.23.

Example C73-fluoro-5-(1-methyl-4-(methylamino)-6-propyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained starting with intermediate C1.5 (20 mg, 0.048 mmol)and ethyl iodide (40 mg, 0.24 mmol) and using the procedure describedfor the synthesis of Example C1. Obtained 7 mg of C7 as a yellow solid.LCMS B: Ret time 3.11 min, (M+H)⁺=363.26.

Example C83-fluoro-5-(6-(2-(2-hydroxyethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

C8.1: tert-butyl7-(3-cyano-5-fluorophenyl)-6-(2,3-dihydroxypropyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C3.1 (480 mg, 1.04 mmol) in THF (10 ml) was treated withN-methylmorpholine N-oxide (257 mg, 2.19 mmol) in 2 ml of water and with500 ul of a 4% aqueous OSO₄ solution. The solution was stirred at roomtemperature for 2 days and then concentrated on a rotary evaporator. Theresidue was dissolved in ethyl acetate and washed with water, a solutionof NaHSO₃ and brine. The solution was concentrated on a rotaryevaporator to give 490 mg of C8.1 as a solid. LCMS B: Ret time 2.61 min,(M+H)⁺=495.23.

C8.2: tert-butyl7-(3-cyano-5-fluorophenyl)-1-methyl-6-(2-oxoethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C8.1 (450 mg, 0.91 mmol) in THF (15 ml) was treated with a5 ml aqueous solution of NaIO₄ (500 mg, 2.34 mmol) and stirred overnightat RT. The solution was diluted with water and extracted into ethylacetate. The extracts were washed with water and brine and concentratedto give 360 mg of C8.2 as a dark solid. This was used without furtherpurification. LCMS B: Ret time 2.91 min. ES⁻: (M−H)⁻=461.29. ¹H NMR, 400MHz, CDCl₃: 9.77 (s, 1H), 7.85 (s, 1H), 7.58 (s, 1H), 7.41 (m, 2H), 6.91(s, 1H), 5.23 (s, 2H), 4.09 (s, 3H), 3.43 (s, 3H), 1.42 (s, 9H).

C8.3: tert-butyl7-(3-cyano-5-fluorophenyl)-6-(2-(2-hydroxyethylamino)ethyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C8.2 (45 mg, 0.097 mmol) in MeOH (5 ml) was treated withethanolamine (85 mg, 1.39 mmol), NaCNBH₃ (20 mg, 0.32 mmol), 1 drop ofAcOH and stirred overnight at RT. The mixture was concentrated and theresidue diluted with 1 N NaOH and extracted into ethyl acetate. Theextracts were washed with water, brine and concentrated to give a solidwhich was chromatographed on silica gel eluting with 5%NH₄OH/MeOH/CH₂Cl₂ (0.5:4.5:95) to give 20 mg of C8.3a as a white solid.LCMS B: Ret time 2.16 min, (M+H)⁺=508.28. ¹H NMR, 400 MHz, CDCl₃: 7.83(s, 1H), 7.75 (s, 1H), 7.63 (dm, 1H), 7.42 (dm, 1H), 6.82 (s, 1H), 4.56(t, J=6 Hz, 2H), 4.10 (s, 3H), 3.49 (s, 3H), 3.49 (m, 2H), 3.01 (t, J=6Hz, 2H), 2.67 (t, J=5 Hz, 2H), 1.46 (s, 9H).

Also obtained from the column was 15 mg of tert-butyl6-(2-cyano-2-(2-hydroxyethylamino)ethyl)-7-(3-cyano-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamateC8.3b as a white solid. LCMS B: Ret time 2.50 min, (M+H)⁺=533.27. ¹HNMR, 400 MHz, CDCl₃: 7.86 (s, 1H), 7.71 (s, 1H), 7.59 (dm, 1H), 7.46(dm, 1H), 6.85 (s, 1H), 4.75 (m, 1H), 4.64 (m, 1H), 4.41 (m, 1H), 4.10(s, 3H), 3.56 (m, 2H), 3.50 (s, 3H), 3.01 (m, 1), 2.67 (m, 1H), 1.49 (s,9H).

C8:3-fluoro-5-(6-(2-(2-hydroxyethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

A solution of C8.3a (20 mg, 0.039 mmol) in CH₂Cl₂ (2 ml) was treatedwith 6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with 1 N NaOH and extracted into CH₂Cl₂ and washed withwater and brine. The solvent was removed under vacuum to give 10 mg ofC8 as yellow solid. LCMS B: Ret time 1.81 min, (M+H)⁺=408.31. ¹H NMR,400 MHz, CDCl₃: 7.68 (s, 1H), 7.62 (s, 1H), 7.53 (dm, 1H), 7.29 (dm,1H), 6.67 (s, 1H), 5.54 (t, J=5 Hz, 1H), 4.49 (t, J=4 Hz, 2H), 4.02 (s,3H), 3.55 (t, J=5 Hz, 2H), 3.20 (d, J=5 Hz, 3H), 3.07 (t, J=6 Hz, 2H),2.73 (t, J=5 Hz, 2H).

Example C93-(6-(2-cyano-2-(2-hydroxyethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

A solution of C8.3b (15 mg, 0.028 mmol) in CH₂Cl₂ (2 ml) was treatedwith 5 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with 1 N NaOH and extracted into CH₂Cl₂ and washed withwater and brine. The solvent was removed under vacuum to give 10 mg ofC9 as yellow solid. LCMS B: Ret time 2.10 min, (M+H)⁺=433.28. ¹H NMR,400 MHz, CDCl₃: 7.66 (bs, 1H), 7.63 (s, 1H), 7.52 (dm, 1H), 7.32 (dm,1H), 6.68 (s, 1H), 5.64 (bt, J=5 Hz, 1H), 4.64-4.45 (m, 3H), 4.02 (s,3H), 3.59 (t, J=5 Hz, 2H), 3.18 (d, J=5 Hz, 3H), 2.93 (m, 1H), 2.72 (m,1H).

Example C103-(6-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

C10.1: tert-butyl7-(3-cyano-5-fluorophenyl)-6-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C1.5 (42 mg, 0.10 mmol) in DMF (5 ml) was treated withCs₂CO₃ (268 mg, 0.8 mmol) and N-(3-bromopropyl)phthalimide (120 mg, 0.45mmol) and heated at 95° C. in an oil bath for 7 hrs. The mixture wasdiluted with ethyl acetate (150 ml) and washed several times with water.The solution was concentrated on a rotary evaporator and the residuechromatographed on silica gel eluting with 75% ethyl acetate/hexane togive 30 mg of C10.1 as a yellow solid. LCMS B: Ret time 3.27 min,(M+H)⁺=608.30.

C10.2:3-(6-(3-(1,3-dioxoisoindolin-2-yl)propyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

A solution of C10.1 (30 mg, 0.05 mmol) in CH₂Cl₂ (2 ml) was treated with6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with sat'd NaHCO₃ and extracted into CH₂Cl₂. The solvent wasevaporated under vacuum and the residue chromatographed on silica geleluting with NH₄OH/MeOH/CH₂Cl₂ (0.5:4.5:95) to give 20 mg of C10.2 asyellow solid. LCMS B: Ret time 2.95 min, (M+H)⁺=508.22.

C10.3:3-(6-(3-aminopropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

A solution of C10.2 (10 mg, 0.02 mmol) in ethanol (6 ml) was treatedwith 1 ml of hydrazine and stirred heated to reflux for 1 hr. Themixture was concentrated on a rotary evaporator and the residueextracted into CH₂Cl₂ and washed with water. The solvent was evaporatedunder vacuum and the residue chromatographed on silica gel eluting withNH₄OH/MeOH/CH₂Cl₂ (1:9:90) to give 4 mg of C10 as yellow solid. LCMS B:Ret time 2.03 min, (M+H)⁺=378.26.

Example C123-fluoro-5-(1-methyl-4-(methylamino)-6-(2-(pyrrolidin-1-yl)ethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.92 min, (M+H)⁺=418.29.

Example C133-fluoro-5-(6-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.86 min, (M+H)⁺=434.29.

Example C143-(6-(2-cyano-2-(3-hydroxypyrrolidin-1-yl)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C9, as a yellow solid. LCMS B: Ret time 2.52 min, (M+H)⁺=459.27.

Example C153-(6-(2-(tert-butylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 2.06 min, (M+H)⁺=420.30.

Example C163-(6-(2-(tert-butylamino)-2-cyanoethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C9, as a yellow solid. LCMS B: Ret time 2.55 min, (M+H)⁺=445.31.

Example C173-(6-(2-(dimethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.82 min, (M+H)⁺=392.30.

Example C183-(6-(2-cyano-2-(dimethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C9, as a yellow solid. LCMS B: Ret time 2.55 min, (M+H)⁺=418.34.

Example C19(S)-3-fluoro-5-(6-(2-(1-hydroxypropan-2-ylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.91 min, (M+H)⁺=422.25.

Example C203-(6-(2-cyano-2-((S)-1-hydroxypropan-2-ylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C9, as a yellow solid (mixture of diastereomers). LCMS B: Rettime 2.29 and 2.22 min, (M+H)⁺=447.25.

Example C21(S)-3-fluoro-5-(6-(2-(1-hydroxybutan-2-ylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.99 min, (M+H)⁺=436.26.

Example C223-(6-(2-cyano-2-((S)-1-hydroxybutan-2-ylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C9, as a yellow solid (mixture of diastereomers). LCMS B: Rettime 2.42 and 2.51 min, (M+H)⁺=461.26.

Example C233-fluoro-5-(6-(2-hydroxyethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

A solution of C8.3 (34 mg, 0.073 mmol) in ethanol (3 ml) was cooled to0-5° C. and NaBH₄ (11 mg, 0.3 mmol) was added. The reaction mixture waswarmed up to RT and stirred for 30 minutes. The reaction was quenchedwith acetone and concentrated to yield a crude product which waspurified on prep HPLC (HPLC: Column: YMC 20×100 mm S-5; Gradient time:10 min; Flow rate=20 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA;Solvent B=90% MeOH —10% water —0.1% TFA; Start % B=20; Final % B=100.)to provide the Boc protected intermediate, which dissolved in CH₂Cl₂(0.25 ml) and added TFA (0.25 ml) dropwise at 0-5° C. The reactionmixture was warmed up to RT, stirred for 10 minutes and concentrated toyield C23 (8 mg, 19%). HPLC: 99%, retention time: 2.277 minute(condition B). LC/MS (M+H)⁺=365, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.29 (1H,s), 7.73 (1H, s), 7.58-7.67 (1H, m), 7.51 (1H, s), 6.94 (1H, s), 4.29(2H, m), 4.05 (3H, s), 3.99-4.03 (2H, m), 3.09 (3H, s).

Example C24 ethyl4-((7-(3-cyano-5-fluorophenyl)-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)methyl)benzoate

This was obtained, using the procedure described for the synthesis ofExample C10, as a yellow solid. LCMS B: Ret time 3.28 min,(M+H)⁺=469.21.

Example C253-fluoro-5-(6-(2-methoxyethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C10, as a yellow solid. LCMS B: Ret time 2.72 min,(M+H)⁺=379.23.

Example C263-(6-(3,4-dihydroxybutyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8.2, as a yellow solid. LCMS B: Ret time 2.28 min,(M+H)⁺=409.23.

Example C273-(6-(3-amino-2-hydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

C27.1: tert-butyl7-(3-cyano-5-fluorophenyl)-1-methyl-6-(oxiran-2-ylmethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C1.5 (300 mg, 0.71 mmol) in DMF (2 ml) was treated withCs₂CO₃ (698 mg, 2.1 mmol) and epibromohydrin (195 mg, 1.4 mmol) andheated at 95° C. in an oil bath for 2 hrs. The mixture was diluted withethyl acetate (150 ml) and washed several times with water. The solutionwas concentrated on a rotary evaporator and the residue chromatographedon silica gel eluting with ethyl acetate/hexane to give 200 mg of C27.1as a solid. LCMS B: Ret time 2.95 min, (M+H)⁺=477.20.

C27.2:3-fluoro-5-(1-methyl-4-(methylamino)-6-(oxiran-2-ylmethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

A solution of C27.1 (100 mg, 0.21 mmol)) in CH₂Cl₂ (2 ml) was treatedwith 6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuechromatographed on silica gel eluting with ethyl acetate to give 22 mgof CC27.2 as yellow solid. LCMS B: Ret time 2.58 min, (M+H)⁺=377.23.

C27:3-(6-(3-amino-2-hydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

A solution of C27.2 (22 mg, 0.06 mmol) in MeOH (2 mL) and 1 mL of NH4OHwas heated in a microwave at 80° C. for 200 seconds. The solution wasconcentrated and chromatographed on silica gel eluting with 10%NH₄OH/MeOH/CH₂Cl₂ to give 8 mg of C27 as yellow solid. LCMS B: Ret time2.17 min, (M+H)⁺=395.26.

Example C283-(6-(2-aminoethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitriletrifluoacetate salt

This was obtained, using the procedure described for the synthesis ofExample C10 and C11, after HPLC purification and lypholization as ayellow solid. LCMS B: Ret time 1.88 min, (M+H)⁺=364.24. ¹H NMR, 500 MHz,CDCl₃/CD₃OD: 7.55 (s, 1H), 7.38 (m, 2H), 7.26 (m, 1H), 6.65 (s, 1H),4.46 (t, J=6 Hz, 2H), 4.09 (s, 3H), 3.51 (t, J=5 Hz, 2H), 3.16 (bs, 3H).

Example 293-fluoro-5-(6-(2-hydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

C29.1: tert-butyl7-(3-cyano-5-fluorophenyl)-6-(2-hydroxypropyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C8.3 (50 mg, 0.10 mmol) in THF (5 ml) was cooled in an icebath and treated with 0.1 ml of a 3 M solution of MeMgBr in ether. Thesolution was stirred at 0° C. for 1.5 hours and then quenched with waterand extracted into ethyl acetate. The extract was washed with water,brine and concentrated to give 50 mg C29.1 as a solid. LCMS B: Ret time2.91 min, (M+H)⁺=479.34.

C29:3-fluoro-5-(6-(2-hydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

A solution of C29.1 (50 mg, 0.10 mmol) in CH₂Cl₂ (2 ml) was treated with6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with sat'd NaHCO3 and extracted into CH₂Cl₂. The solvent wasevaporated under vacuum and the residue chromatographed on silica geleluting with NH₄OH/MeOH/CH₂Cl₂ (0.5:2.5:97) to give 20 mg of C29 asyellow solid. LCMS B: Ret time 2.51 min, (M+H)⁺=379.24. ¹H NMR, 400 MHz,CDCl₃: 7.64 (s, 1H), 7.54 (s, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 6.67 (s,1H), 5.72 (bs, 1H), 4.38 (m, 1H), 4.21 (m, 2H), 4.02 (s, 3H), 3.17 (d,J=5 Hz, 3H), 1.28 (d, 7 Hz, 3H).

Example C307-(3-(aminomethyl)-5-fluorophenyl)-N,1,6-trimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

C30.1: tert-butyl7-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A slurry of Raney-Nickel (1 g) was put in a Parr bottle and rinsed withethanol and decanted. Then a solution of C1.5 (330 mg, 0.78 mmol) in 20ml of ethanol and 3 ml of aqueous NH₄OH was added and the mixturehydrogenated overnight at 50 psi in a Parr shaker. The mixture wasfiltered and concentrated to give 320 mg of C30.1 as a light yellowsolid. This was used without further purification. LCMS B: Ret time 2.16min, (M+H)⁺=425.27.

C30.2: tert-butyl7-(3-(tert-butoxycarbonylaminomethyl)-5-fluorophenyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C30.1 (320 mg, 0.78 mmol) in THF (20 ml) was treated withEt₃N (140 mg, 0.94 mmol), di-tert-butyl dicarbonate (240 mg, 1.1 mmol)and stirred at room temperature for 2 hours. The solvent removed undervacuum and the residue dissolved in ethyl acetate and washed with water,1N NaOH, and brine. The solvent removed under vacuum to give 390 mg ofC30.2 as a yellow solid. This was used without further purification.LCMS B: Ret time 3.24 min, (M+H)⁺=525.36.

C30.3: tert-butyl7-(3-(tert-butoxycarbonylaminomethyl)-5-fluorophenyl)-1,6-dimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C30.2 (48 mg, 0.09 mmol) in DMF (3 ml) was treated withCs₂CO₃ (59 mg, 0.18 mmol) and MeI (40 mg, 0.18 mmol) and stirred at roomtemperature for 2 hours. The mixture was diluted with water andextracted into ethyl acetate. The extract was washed with water,concentrated and the residue chromatographed on silica gel, eluting withethyl acetate to give 30 mg of C30.3 as a yellow solid. LCMS B: Ret time3.39 min, (M+H)⁺=539.32.

C30:7-(3-(aminomethyl)-5-fluorophenyl)-N,1,6-trimethyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

A solution of C30.3 (30 mg, 0.056 mmol) in CH₂Cl₂ (2 ml) was treatedwith 6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with sat'd NaHCO₃ and extracted into CH₂Cl₂. The solvent wasevaporated under vacuum and the residue chromatographed on silica geleluting with NH₄OH/MeOH/CH₂Cl₂ (1:9:90) to give 12 mg of C30 as yellowsolid. LCMS B: Ret time 1.92 min, (M+H)⁺=339.29. ¹H NMR, 400 MHz,CDCl₃/CD₃OD: 7.65 (s, 1H), 7.33 (s, 1H), 7.20 (m, 1H), 7.06 (m, 1H),6.67 (s, 1H), 4.03 (s, 3H), 4.01 (s, 2H), 3.90 (s, 3H), 2.97 (s, 3H).

Example C31(S)-3-(7-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)propane-1,2-diol

C31.1: (S)-tert-butyl7-(3-(tert-butoxycarbonylaminomethyl)-5-fluorophenyl)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C30.2 (48 mg, 0.09 mmol) in DMF (3 ml) was treated withCs₂CO₃ (60 mg, 0.18 mmol) and (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl4-methylbenzenesulfonate (85 mg, 0.29 mmol) and heated in an oil bath at95° C. for 3 hours. The mixture was diluted with water and extractedinto ethyl acetate. The extract was washed with water, concentrated andthe residue chromatographed on silica gel, eluting with ethyl acetate togive 20 mg of C31.1 as a yellow solid. LCMS B: Ret time 3.48 min,(M+H)⁺=639.34.

C31:(S)-3-(7-(3-(aminomethyl)-5-fluorophenyl)-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)propane-1,2-diol

A solution of C31.1 (30 mg, 0.056 mmol) in CH₂Cl₂ (2 ml) was treatedwith 6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with sat'd NaHCO₃ and extracted into CH₂Cl₂. The solvent wasevaporated under vacuum and the residue chromatographed on silica geleluting with NH₄OH/MeOH/CH₂Cl₂ (1:9:90) to give 8 mg of C31 as yellowsolid. LCMS B: Ret time 1.63 min, (M+H)⁺=399.28.

Example C32(S)-3-(7-cyclohexyl-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)propane-1,2-diol

C32.1: tert-butyl6-amino-7-(cyclohexylethynyl)-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate

A1.12tert-Butyl-6-amino-7-iodo-1-methyl-1H-imidazo[4,5-c]pyridin-4-yl(methyl)carbamate(1.0 g, 2.48 mmol), dichlorobis(triphenylphosphine)palladium (75 mg,0.11 mmol), ethynylcyclohexane (0.3 g, 2.8 mmol), CuI (25 mg, 0.13mmol), and diisopropylamine (5 mL) were added to N,N-dimethylformamide(7 mL). The reaction mixture was heated at 95° C. (in preheated oilbath) for 60 min. Additional ethynylcyclohexane (0.3 g, 2.8 mmol) wasadded to the reaction mixture and heated for another 60 min. Thereaction was cooled and diluted with ethyl acetate and washed severaltimes with water. The solvent removed under reduced pressure and theresidue was chromatographed on a silica gel column (50%-70% ethylacetate/hexane) to give 400 mg of C32.1 as a yellow solid. LCMS B: Rettime 3.15 min, (M+H)⁺=384.41.

C32.2: tert-butyl7-cyclohexyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C32.1 (300 mg, 0.78 mmol) in DMA (8 ml) was treated withsolid potasium t-butoxide (123 mg, 1.1 mmol) and heated at 85° C. (inpreheated oil bath) for 3 hours. The reaction was cooled and dilutedwith ethyl acetate and washed several times with water. The solventremoved under reduced pressure and the residue was chromatographed on asilica gel column (75-100% ethyl acetate/hexane) to give 180 mg ofC32.2. LCMS B: Ret time 2.99 min, (M+H)⁺=384.37.

C32.3: (S)-tert-butyl7-cyclohexyl-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C32.2 (180 mg, 0.47 mmol) in DMF (5 ml) was treated withCs₂CO₃ (450 mg, 1.38 mmol) and(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (400mg, 1.4 mmol) and heated in an oil bath at 95° C. for 8 hours. Themixture was diluted with water and extracted into ethyl acetate. Theextract was washed with water, concentrated and the residuechromatographed on silica gel, eluting with ethyl acetate to give 130 mgof C32.3 as a yellow solid. LCMS B: Ret time 3.48 min, (M+H)⁺=498.42.

C32:(S)-3-(7-cyclohexyl-1-methyl-4-(methylamino)imidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl)propane-1,2-diol

A solution of C32.3 (130 mg, 0.26 mmol) in CH₂Cl₂ (2 ml) was treatedwith 6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with sat'd NaHCO₃ and extracted into CH₂Cl₂. The solvent wasevaporated under vacuum and the residue chromatographed on silica geleluting with 5% NH₄OH/MeOH/CH₂Cl₂ to give 80 mg of C32 as yellow solid.LCMS B: Ret time 2.47 min, (M+H)⁺=358.37.

Example C33(S)-3-(6-(2,3-dihydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

C33.1: (S)-tert-butyl7-(3-cyano-5-fluorophenyl)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C1.5 (150 mg, 0.36 mmol) in DMF (5 ml) was treated withCs₂CO₃ (450 mg, 1.38 mmol) and(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (310mg, 1.1 mmol) and heated in an oil bath at 95° C. for 8 hours. Themixture was diluted with water and extracted into ethyl acetate. Theextract was washed with water, concentrated and the residuechromatographed on silica gel, eluting with 75% ethyl acetate/hexane togive 180 mg of C33.1 as a yellow solid. LCMS B: Ret time 3.24 min,(M+H)⁺=535.27.

C33:(S)-3-(6-(2,3-dihydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

A solution of C33.1 (160 mg, 0.30 mmol) in CH₂Cl₂ (2 ml) was treatedwith 6 ml of TFA and stirred at room temperature for 1 hr. The mixturediluted with CH₂Cl₂ and concentrated on a rotary evaporator. The residuewas treated with sat'd NaHCO₃ and extracted into CH₂Cl₂. The solvent wasevaporated under vacuum and the residue chromatographed on silica geleluting with NH₄OH/MeOH/CH₂Cl₂ (0.5:4.5:95) to give 90 mg of C33 asyellow solid. LCMS B: Ret time 2.16 min, (M+H)⁺=395.27. Chiral HPLCRetention time: 6.97 min. Chiral HPLC conditions: Column: Chiralpak AD250×4.6 mm ID, 10 μm; Mobil Phase: Hex/MeOH/IPA/DEA=30:35:35:0.1; Flowrate: 1.0 ml/min; UV detection: 220 nm. ¹H NMR, 500 MHz, CDCl₃: 7.65 (s,1H), 7.62 (s, 1H), 7.46 (m, 1H), 7.33 (m, 1H), 6.68 (s, 1H), 5.73 (bs,1H), 4.48 (m, 1H), 4.29 (m, 1H), 4.09 (m, 1H), 4.04 (s, 3H), 3.58 (m,2H), 3.19 (d, J=5 Hz, 3H), 1.61 (bs, 3H).

Example C34(R)-3-(6-(2,3-dihydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained using the procedure describe for Example C33 exceptusing (S)(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonateto give C34 as a yellow solid. LCMS B: Ret time 2.16 min, (M+H)⁺=395.28.Chiral HPLC Retention time: 5.52 min. Chiral HPLC conditions: Column:Chiralpak AD 250×4.6 mm ID, 10 μm; Mobil Phase:Hex/MeOH/IPA/DEA=30:35:35:0.1; Flow rate: 1.0 ml/min; UV detection: 220nm.

Alternate Preparation of C33 and C34

C8.2 (20 mg, 0.04 mmol) was subjected to chiral separation (Chiralpak AD500×20 mm ID; 10 um, Hex/EtOH/IPA/DEA=82:9:9:0.1; 25 ml/min) to yield aBoc protected product. It was dissolved in CH₂Cl₂ (0.25 ml) and addedTFA (0.25 ml) dropwise at 0-5° C. The reaction mixture was warmed up toRT, stirred for 10 minutes and concentrated to yield C33 (8 mg, 78%).HPLC: 85%, retention time: 2.115 minute (condition B). ChiralHPLC: >99.9% ee. retention time: 5.577 minute (Chiralpak AD 10 um4.6×250 mm; Hex/MeOH/IPA/DEA=30/37.5/37.5/0.1; 1.0 ml/min). LC/MS(M+H)⁺=395, ¹H-NMR (400 MHz, CD₃OD) δ ppm 8.12 (1H, s), 7.76 (1H, s),7.67 (1H, d, J=9.16 Hz), 7.49 (1H, d, J=7.12 Hz), 6.94 (1H, s), 4.42(1H, d, J=12.21 Hz), 4.09-4.20 (1H, m), 3.99-4.07 (4H, m), 3.45-3.56(1H, m), 3.38 (1H, dd, J=11.19, 6.61 Hz), 3.08 (3H, s) and C34 HPLC:85%, retention time: 2.113 minute (condition B). Chiral HPLC: 90% ee.retention time: 7.394 minute (Chiralpak AD 10 um 4.6×250 mm;Hex/MeOH/IPA/DEA=30/37.5/37.5/0.1; 1.0 ml/min). LC/MS (M+H)⁺=395, ¹H-NMR(400 MHz, CD₃OD) δ ppm 8.11 (1H, s), 7.76 (1H, s), 7.67 (1H, d, J=8.65Hz), 7.49 (1H, d, J=111.70 Hz), 6.94 (1H, s), 4.42 (1H, d, J=12.21 Hz),4.13 (1H, d, J=11.19 Hz), 3.99-4.07 (4H, m), 3.51 (1H, d, J=113.23 Hz),3.37 (1H, s), 3.08 (3H, s).

Example C353-fluoro-5-(6-(2-(2-methoxyethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.96 min, (M+H)⁺=422.35.¹H NMR, 500 MHz, CDCl₃: 7.71 (s, 1H), 7.61 (s, 1H), 7.58 (dm, 1H), 7.29(dm, 1H), 6.65 (s, 1H), 5.51 (m, 1H), 4.46 (t, J=6 Hz, 2H), 4.01 (s,3H), 3.41 (t, J=5 Hz, 2H), 3.20 (d, J=5 Hz, 3H), 3.08 (t, J=6 Hz, 2H),2.74 (t, J=5 Hz, 2H).

Example C363-(6-(2-cyano-2-(2-methoxyethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C9, as a yellow solid. LCMS B: Ret time 2.41 min, (M+H)⁺=447.27.¹H NMR, 500 MHz, CDCl₃: 7.66 (bs, 2H), 7.55 (dm, 1H), 7.344 (dm, 1H),6.67 (s, 1H), 5.64 (m, 1H), 4.57 (m, 3H), 4.03 (s, 3H), 3.44 (m, 2H),3.30 (s, 3H), 3.19 (m, 3H), 2.93 (m, 1H), 2.75 (m, 1H).

Example C373-fluoro-5-(6-(2-((2-hydroxyethyl)(methyl)amino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.81 min, (M+H)⁺=422.30.

Example C383-(6-(2-(1,3-dihydroxypropan-2-ylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-dipyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.83 min, (M+H)⁺=438.28.

Example C393-fluoro-5-(1-methyl-4-(methylamino)-6-(2-morpholinoethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.83 min, (M+H)⁺=434.32.

Example C403-fluoro-5-(1-methyl-4-(methylamino)-6-(2-(piperazin-1-yl)ethyl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 2.00 min, (M+H)⁺=433.33.

Example C413-(6-(2-(bis(2-hydroxyethyl)amino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazol-4,5-d]pyrrolo[2,3-b]pyridin-7-yl)-5-fluorobenzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.82 min, (M+H)⁺=452.30.

Example C423-fluoro-5-(6-(2-(2-(2-hydroxyethoxy)ethylamino)ethyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)benzonitrile

This was obtained, using the procedure described for the synthesis ofExample C8, as a yellow solid. LCMS B: Ret time 1.88 min, (M+H)⁺=452.33.

Example C431,6-dihydro-N,1,6-trimethyl-7-phenyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

Sodium bis(trimethylsilyl)amide (0.11 mL of a 1.0M THF solution, 0.11mmol) was added to a solution of A1.14 (20.0 mg, 0.053 mmol) in DMF(0.70 mL) at 0° C. After 10 min., iodomethane was added (16.2 μL, 0.053mmol), the flask was sealed, and stirring at 0° C. was continued for 25min. The reaction mixture was concentrated under vacuum. TFA was added(2.0 mL), followed by heating at 50° C. for 35 min. TFA was removedunder vacuum. The crude product was purified by reversed-phasepreparative HPLC and trituration with ether to yield 10.8 mg of C43 asan off-white solid (50% assuming 1.0 TFA salt). HPLC (C): 95.0%, ret.Time 2.73 min., LC/MS (M+H)⁺=292.32.

Example C446-ethyl-1,6-dihydro-N,1-dimethyl-7-phenyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-amine

Sodium bis(trimethyl)amide (0.10 mL of a 1.0M solution in THF, 0.10mmol) was added to a solution of A1.14 (15.0 mg, 0.040 mmol) in DMF(0.60 mL) at 0° C. under Ar. After 20 min., iodoethane was added (15.9μL, 0.20 mmol), and stirring was continued at room temperature for 50min. DMF was removed under vacuum. TFA was added (2.0 mL), and thereaction mixture was stirred at 50° C. for 30 min. TFA was removed undervacuum. The crude product was purified by reversed-phase preparativeHPLC to yield 13.2 mg of C44 as a pale green solid which was suspendedin ether, sonicated briefly, collected by filtration, and rinsed withether. Yield after drying: 4.20 mg of C44 as an off-white solid (21%assuming a 1.0 TFA salt). HPLC (C): 96.1%, ret. Time 2.97 min., LC/MS(M+H)⁺=306.35.

Example C453-[1-methyl-4-(methylamino)-7-phenylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl]-1,2-propanediol

C45.1: tert-butyl6-allyl-1-methyl-7-phenyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

Sodium bis(trimethyl)amide (0.81 mL of a 10M solution in THF, 0.81 mmol)was added to a solution of A1.14 (0.17 g, 0.045 mmol) in DMF (13.6 mL)at 0° C. under Ar. After 20 min., allyl bromide was added (0.16 mL, 1.85mmol), and stirring was continued at room temperature for 45 min. Thereaction was quenched with saturated aqueous NH₄Cl solution (0.20 mL),and DMF was removed under vacuum. The residue was partitioned between2:1 EtOAc:THF (40.0 mL) and water (10 mL). After separation, the organiclayer was washed with water, brine, dried (Na₂SO₄), and concentratedunder vacuum to yield 0.22 g of a viscous tan oil. Flash chromatographyon silica gel, eluting with an EtOAc:hexane gradient followed byEtOAc:MeOH yielded C45.1 (0.1345 g, 72%) as a solid. HPLC (C): 92.3%,ret. Time 3.32 min., LC/MS (M+H)⁺=418.4.

C45.2: tert-butyl6-(2,3-dihydroxypropyl)-1-methyl-7-phenyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

A solution of C45.1 (120.6 mg, 0.29 mmol), 4-methylmorpholine-N-oxide(0.10 g, 0.87 mmol), and OsO₄ (0.24 mL of a 2% aqueous solution) in THF(3.26 mL) and water (0.60 mL) was stirred for 16 h. Saturated aqueousNaHCO₃ solution was added (2.0 mL), and the reaction mixture was stirredfor 30 min. EtOAc and water were added; after separation, the aqueouslayer was extracted with EtOAc, the combined organic layers were washedwith water (3×), brine, dried (Na₂SO₄), and evaporated under vacuum toyield 124.5 mg of C45.2 as a pale yellow solid (95%).

C45.3:3-[1-methyl-4-(methylamino)-7-phenylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-6(1H)-yl]-1,2-propanediol

A solution of C45.2 (10.0 mg, 0.022 mmol) in TFA (1.0 mL) was stirred at0° C. to room temperature for 25 min. TFA was removed under vacuum. Thecrude product was triturated with ether to yield C45 as a pale tan solid(5.0 mg, 49%, assuming a 1.0 TFA salt). HPLC): 93.5%, ret. time 2.15min., LC/MS (M+H)⁺=352.35.

Example C461-methyl-4-(methylamino)-7-phenyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-ethanol

C46.1: tert-butylmethyl(1-methyl-6-(2-oxoethyl)-7-phenyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl)carbamate

A solution of NaIO₄ (78.94 mg, 0.37 mmol) in water (1.25 mL) was addedslowly to a solution of C45.2 (0.11 g, 0.246 mmol) in acetone (4.85 mL)at 0° C. After 16 h at 0° C., more NaIO₄ was added (26.31 mg, 0.12mmol), followed by the same amount several hours later. Water (1.25 mL),acetone (4.0 mL), and MeOH (1.0 mL) were added, and stirring wascontinued at room temperature for 2 days. The reaction mixture wasdiluted with water and EtOAc. After separation, the aqueous layer wasextracted with EtOAc, the combined organic layers were washed withwater, brine, dried (Na₂SO₄), and evaporated under vacuum to yield 0.12g of a viscous tan oil. Trituration with 80:20 ether:hexane yieldedC46.1 as an off white solid (61.6 mg, 59%). HPLC (C): 93.4%, ret. time2.86 min., LC/MS (M+H)⁺=420.40.

C46.2: tert-butyl6-(2-hydroxyethyl)-1-methyl-7-phenyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-yl(methyl)carbamate

Sodium borohydride (8.9 mg, 0.24 mmol) was added to a solution of C46.1(25.0 mg, 0.06 mmol) in EtOH (3.0 mL). The reaction mixture was stirredfor 1.25 hr. EtOH was removed under vacuum. Saturated aqueous KHSO₄solution was slowly added at 0° C. with stirring until H₂ gas evolutionceased. After several minutes, NaHCO₃ was slowly added at 0° C. to pH8.5. EtOAc was added. After separation, the EtOAc layer was washed withwater, brine, dried (Na₂SO₄), and evaporated under vacuum to yield 20.6mg of C46.2 as an oily solid (81%). HPLC (C): 93.4%, ret. time 2.77min., LC/MS (M+H)⁺=422.41

C46.3:1-methyl-4-(methylamino)-7-phenyl-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-6(1H)-ethanol

TFA (1.5 mL) was added to C46.2 (20.6 mg) at 0° C. The ice bath wasremoved and the reaction mixture was stirred for 20 min. TFA was removedunder vacuum and the crude product was triturated with 70:30ether:hexane to yield 15.90 mg of C46 as a white solid (75% assuming a1.0 TFA salt). HPLC (C): 95.0%, ret. time 2.35 min., LC/MS (M+H)⁺=322.3.

Example C47(R)-N-((6-(6-(2,3-dihydroxypropyl)-1-methyl-4-(methylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)-2-methoxyacetamide

To a solution of A228.5 (50 mg, 0.104 mmol) in DMF (1 mL) at roomtemperature was added tBuOK/THF (1 M, 0.136 mL, 0.136 mmol) followed 5minutes later by the addition of(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (90mg, 0.392 mmol) in one portion. The reaction was heated to 60° C. withstirring overnight. Water (0.1 mL) was added to quench the reaction andthe solution was evaporated to near dryness under a stream of nitrogenthen dissolved in methanol and purified by preparative reverse phaseHPLC to afford a mixture of protected and deprotected products alongwith Tosyl starting material. The mixture was treated with neattrifluoroacetic acid at room temperature for 5 minutes then evaporatedto dryness. The residue was dissolved in methanol and purified bypreparative reverse phase HPLC followed by evaporation and purificationof the resulting residue on an SCX column (eluting with 1N NH₃/MeOH) toafford C47 as a yellow solid (4.9 mg). The compound had an HPLCretention time=2.08 min. (Column: Chromolith SpeedROD 4.6×50 mm—4 min.;Solvent A=10% MeOH, 90% H₂O, and 0.2% H₃PO₄; Solvent B=90% MeOH, 10%H₂O, and 0.2% H₃PO₄) and a LC/MS M+H⁺=454.2

The examples described in Table Cl were prepared in a manner similar tothat of Example C47. TABLE C1 HPLC Retention MS Ex. R Name (min)Reported C48

(S)-N-((6-(6-(2,3- dihydroxypropyl)-1-methyl-4- (methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)-2- methoxyacetamide 2.08 454.2 C49

N-((6-(6-(2-hydroxyethyl)-1- methyl-4-(methylamino)-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-7-yl)pyridin-2-yl)methyl)-2- methoxyacetamide 2.05 424.3 C50

N-((6-(6-allyl-1-methyl-4- (methylamino)-1,6- dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-7- yl)pyridin-2-yl)methyl)-2- methoxyacetamide2.54 420.3 C51

6-allyl-7-(6- (aminomethyl)pyridin-2-yl)- N,1-dimethyl-1,6-dihydroimidazo[4,5- d]pyrrolo[2,3-b]pyridin-4- amine 1.83 348.3

Utility

Compounds herein are inhibitors of IKK. Accordingly, compounds offormula (I) have utility in treating conditions were a decrease in NF-κBactivity would be beneficial. Such conditions include diseases ordisorders in which cytokine levels are modulated as a consequence ofintracellular signaling via IKK, and in particular, diseases that areassociated with an overproduction of cytokines IL-1, IL-4, IL-8, andTNF-α. As used herein, the terms “treating” or “treatment” encompassresponsive and/or prophylaxis measures addressed to the disease stateand/or its sypmtoms, e.g., measures designed to inhibit or delay theonset of the disease or disorder, achieve a full or partial reduction ofthe symptoms or disease state, and/or alleviate, lessen, or cure thedisease and/or its symptoms. When reference is made herein to inhibitionof “IKK,” this means that either or both IKK-2 and IKK-1 are inhibited.

In view of their activity as inhibitors of IKK, compounds of Formula (I)are useful in treating inflammatory diseases, autoimmune diseases,destructive bone disorders, proliferative disorders, angiogenicdisorders, infectious diseases, neurodegenerative diseases, viraldiseases, and ischemia reperfusion conditions.

More particularly, the compounds may be used to treat inflammatorydiseases including, but not limited to, arthritis (e.g., rheumatoidarthritis, lyme disease arthritis, osteoarthritis, traumatic arthritis,rubella arthritis, psoriatic arthritis, gouty arthritis, and otherarthritic conditions); glomerulonephritis, pancreatitis (acute orchronic), diabetes, diabetic retinopathy, macular degeneration,conjunctivitis, aplastic anemia, thrombocytopenia, gastritis, chronicthyroiditis, chronic active hepatitis, multiple sclerosis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, cachexia (includingcachexia secondary to infection, cancer, or heart disease), periodontaldisease, Alzheimer's disease, Parkinson's disease, keloid formation,pulmonary sarcoidosis, myasthenia gravis, inflammatory reaction inducedby endotoxin, Reiter's syndrome, gout, acute synovitis, diseasescharacterized by massive neutrophil infiltration, ankylosingspondylitis, influenze, cerebral malaria, silicosis, bone resorptiondisease, fever, myalgias due to infection, osteoporosis, multiplemyeloma-related bone disorder, neurodegenerative disease caused bytraumatic injury, and traumatic brain injury.

The compounds may also be used to treat acute or chronic graft vs hostreactions (e.g., pancreatic islet allograft), acute or chronictransplant rejection (e.g., kidney, liver, heart, lung, pancreas, bonemarrow, cornea, small bowel, skin allografts, skin homografts,heterografts, and/or cells derived from such organs), and skinconditions including, but not limited to scar tissue formation, eczema,atopic dermatitis, contact dermatitis, urticaria, schleroderma,scleraclerma, and psoriasis. The inventive compounds also may be used totreat allergies and respiratory conditions, including asthma, acuterespiratory distress syndrome, hayfever, allergic rhinitis, and anychronic pulmonary inflammatory disease such as chronic obstructivepulmonary disease. The compounds further may be used to treat steroidresistance in asthma and allergies.

Additionally, the compounds may be used to treat inflammation associatedwith autoimmune diseases including, but not limited to, systemic lupuserythematosis, Addison's disease, autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome), and Grave's disease. Theinventive compounds may be used to infectious diseases such as sepsis,septic shock, Shigellosis, and Heliobacter Pylori.

The compounds may be used to treat viral diseases including herpessimplex type 1 (HSV-1), herpes simplex type 2 (HSV-2), cytomegalovirus,Epstein-Barr, human immunodeficiency virus (HIV), acute hepatitisinfection (including hepatitis A, hepatits B, and hepatitis C), HIVinfection and CMV retinitis, AIDS/ARC or malignancy, and herpes.

The compounds also may be used to treat angiogenic disorders includingsolid tumors, ocular neovasculization, and infantile haemangiomas.

In addition, the compounds may be used to treat Lupus, MultipleScelrosis, Alzheimer's disease, Cachexia, Hodgkin's disease, Stroke,Diabetes, Osteoporosis, Osteoarthritis, Alkylosing spondylitis,Psoriasis, Atopic dermatitis, Atherosclerosis, restenosis,Glomerulonephritis, Inflammation associated with infection and certainviral infections including AIDS, Adult respiratory distress syndrome,Ataxia telangiestasia

In addition, IKK inhibitors omay inhibit the expression of induciblepro-inflammatory proteins such as prostaglandin endoperoxide synthase-2(PGHS-2), also referred to as cyclooxygenase-2 (COX-2). Accordingly,additional conditions that may be treated with the inventive compoundsinclude edema, analgesia and pain, such as neuromuscular pain, headache,pain caused by cancer or surgery, dental pain and arthritis pain. Inview of their COX-2 inhibitory activity, the inventive compounds alsomay be used to treat cancer including without limitation epithelialcancer and adenocarcinoma.

In addition, IKK (+/−) mice when fed a high fat diet have reducedinsulin levels and reduced blood glucose levels. Accordingly compound ofthis invention are useful in the treatment of Type II diabetes (alsoknown as non-insulin dependant diabetes).

Additionally, the compounds are useful to treat ischemia, includingischemia resulting from vascular occlusion, cerebral infarction, stroke,and related cerebral vascular diseases (including cerebrovascularaccident and transient ischemic attack). Accordingly, the compounds maybe used to treat myocardial infarction, coronary artery disease, non-Qwave MI, congestive heart failure, ventricular hypertrophy, cardiacarrhythmias, unstable angina, chronic stable angina, Prinzmetal'sangina, high blood pressure, intermittent claudication, silent ischemia,cardiac hypertrophy, and peripheral occlusive arterial disease (e.g.,peripheral arterial disease, critical leg ischemia, prevention ofamputation, and prevention of cardiovascular morbidity such as MI,stroke or death).

Additionally, in view of their activity in treating ischemia, thecompounds may be useful to treat symptoms or consequences occurring fromthrombosis, atherosclerosis, peripheral arterial disease, and thromboticor thromboembolic symptoms or consequences associated with and/or causedby one or more of the following: thromboembolic stroke (including thatresulting from atrial fibrillation or from ventricular or aortic muralthrombus), venous thrombosis (including deep vein thrombosis), arterialthrombosis, cerebral thrombosis, pulmonary embolism, cerebral embolism,thrombophilia (e.g., Factor V Leiden, and homocystinenimia), coagulationsyndromes and coagulopathies (e.g., disseminated intravascularcoagulation), restenosis (e.g., following arterial injury inducedendogenously or exogenously), atrial fibrillation, and ventricularenlargement (including dilated cardiac myopathy and heart failure). Thecompounds of the invention also may be used to treat symptoms orconsequences of atherosclerotic diseases and disorders, such asatherosclerotic vascular disease, atherosclerotic plaque rupture,atherosclerotic plaque formation, transplant atherosclerosis, andvascular remodeling atherosclerosis. The compounds of the inventionfurther may be used to treat symptoms or consequences of thrombotic orthromboembolic conditions associated with cancer, surgery, inflammation,systematic infection, artificial surfaces (such as stents, bloodoxygenators, shunts, vascular access ports, vascular grafts, artificialvalves, etc.), interventional cardiology such as percutaneoustransluminal coronary angioplasty (PTCA), immobility, medication (suchas oral contraceptives, hormome replacement therapy, and heparin),pregnancy and fetal loss, and diabetic complications includingretinopathy, nephropathy, and neuropathy.

The compounds may be used for the preservation of tissue, for example,the preservation of tissue as relates to organ transplantation andsurgical manipulation. The compounds may be used to treat diseases ordisorders in other tissues or muscles that are associated with ischemicconditions and/or to enhance the strength or stability of tissue andmuscles. For example, the compounds may be used to treat muscle celldamage and necrosis and/or to enhance athletes' performance.

Additional diseases and disorders that may be treated with the inventivecompounds include irritable bowel syndrome, leukemia, CNS disordersassociated with cerebral ischemia, such as cerebral infarction, cerebraledema and the like, and diseases associated with proliferation of smoothmuscle cells, mesangial cells, and fibroblasts. Such diseases includerenal fibrosis, hepatic fibrosis, prostate hypertrophy, and pulmonaryfibrosis.

The compounds also may be used to treat veterinary viral infections,such as lentivirus infections, including, but not limited to, equineinfectious anemia virus; or retro virus infections, including felineimmunodeficiency virus, bovine immunodeficiency virus, and canineimmunodeficiency virus.

The compounds also may be used in treating oncological diseases, intreating cancer and tumors, such as solid tumors, lymphomas andleukemia, and in particular, breast cancer, prostate cancer, andHodgkin's lymphoma.

Additionally this invention relates to a pharmaceutical composition ofcompound of formula I, or pharmaceutically acceptable salt or hydratethereof, and a pharmaceutically acceptable carrier in the treatment ofhyperproliferative disorder in mammal. In particular, the saidpharmaceutical composition is expected to inhibit the growth of thoseprimary and recurrent solid or liquid tumors which are associated withIKK, especially those tumors which are significantly dependent on IKKfor their growth and spread, including for example, hematopoietictumors, cancers of the bladder, squamous cell, head, colorectal,oesophageal, gynecological (such as ovarian), pancreas, breast,prostate, lung, vulva, skin, brain, genitourinary tract, lymphaticsystem (such as thyroid), stomach, larynx and lung.

More specifically, the compounds of formula I are useful in thetreatment of a variety of cancers, including (but not limited to) thefollowing:

-   -   carcinoma, including that of the bladder, breast, colon, kidney,        liver, lung, including small cell lung cancer, esophagus, gall        bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,        and skin, including squamous cell carcinoma;    -   tumors of the skin, including melanoma;    -   hematopoietic tumors including those of lymphoid lineage,        including leukemia, acute lymphocytic leukemia, acute        lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma,        Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma        and Burkett's lymphoma;    -   hematopoietic tumors of myeloid lineage, including acute and        chronic myelogenous leukemias, myelodysplastic syndrome and        promyelocytic leukemia;    -   hematopoietic tumors including those of plasma cell lineage such        as multiple myeloma;    -   tumors of mesenchymal origin, including fibrosarcoma and        rhabdomyosarcoma;    -   tumors of the central and peripheral nervous system, including        astrocytoma, neuroblastoma, glioma and schwannomas; and    -   other tumors, including melanoma, seminoma, teratocarcinoma,        osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid        follicular cancer and Kaposi's sarcoma.

Additionally, the compounds of formula I are useful in the treatment ofthe following cancers.

Breast and other cancers: Hu, M C-T, and Hung, M C. “Role of IkB kinasein tumorigenesis” Future Oncology (2005) 1(1), 67-78.

Colon, lung, and other cancers: Jun-Li Luo, Hideaki Kamata, and MichaelKarin. “IKK/NF-κB signaling: balancing life and death—a new approach tocancer therapy” J Clin Invest. 2005 115(10): 2625-2632.

Colon, lung, stomach, oesophagus, ovarian and other cancers: MichaelKarin1 & Florian R. Greten2 “NF-κB: LINKING INFLAMMATION AND IMMUNITY TOCANCER DEVELOPMENT AND PROGRESSION” Nature Reviews Immunology 5, 749-759(2005).

Lung, pancreatic, colon and other cancers: Greten F R, Karin M. “TheIKK/NF-kappaB activation pathway-a target for prevention and treatmentof cancer.” Cancer Lett. 2004; 206(2):193-9.

Multiple Myeloma: Hideshima T, Chauhan D, Richardson P, Mitsiades C,Mitsiades N, Hayashi T, Munshi N, Dang L, Castro A, Palombella V, AdamsJ, Anderson KC. “NF-kappa B as a therapeutic target in multiplemyeloma.” J Biol. Chem. 2002; 277(19):16639-47.

Lymphoma: Lam L T, Davis R E, Pierce J, Hepperle M, Xu Y, Hottelet M,Nong Y, Wen D, Adams J, Dang L, Staudt L M. “Small molecule inhibitorsof IkappaB kinase are selectively toxic for subgroups of diffuse largeB-cell lymphoma defined by gene expression profiling.” Clin Cancer Res.2005; 11(1):28-40.

Melanoma: Burke J R. “Targeting I kappa B kinase for the treatment ofinflammatory and other disorders.” Curr Opin Drug Discov Devel. 2003;6(5):720-8. and a paper in press: Jinming Yang, Katayoun I. Amiri, JamesR. Burke, Johannes A. Schmid, and Ann Richmond. “BMS-345541 TargetsIkappaB Kinase to Induce Apoptosis in Melanoma: Involvement of NuclearFactor-kappaB and Mitochondria Pathways.” Clin. Cancer Res., in press.The above references are hereby incorporated by reference.

Compounds of formula I may induce or inhibit apoptosis. The apoptoticresponse is aberrant in a variety of human diseases. Compounds offormula I, as modulators of apoptosis, will be useful in the treatmentof cancer (including but not limited to those types mentionedhereinabove), viral infections (including but not limited to herpevirus,poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus), preventionof AIDS development in HIV-infected individuals, autoimmune diseases(including but not limited to systemic lupus, erythematosus, autoimmunemediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, and autoimmune diabetes mellitus),neurodegenerative disorders (including but not limited to Alzheimer'sdisease, AIDS-related dementia, Parkinson's disease, amyotrophic lateralsclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellardegeneration), myelodysplastic syndromes, aplastic anemia, ischemicinjury associated with myocardial infarctions, stroke and reperfusioninjury, arrhythmia, atherosclerosis, toxin-induced or alcohol relatedliver diseases, hematological diseases (including but not limited tochronic anemia and aplastic anemia), degenerative diseases of themusculoskeletal system (including but not limited to osteoporosis andarthritis) aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

The compounds of formula I are especially useful in treatment of tumorshaving a high incidence of IKK kinase activity, such as melanomas, andmultiple myeloma. By the administration of a composition (or acombination) of the compounds of this invention, development of tumorsin a mammalian host is reduced.

Also provided is a pharmaceutical composition comprising a compound offormula I in combination with pharmaceutically acceptable carrier and ananti-cancer or cytotoxic agent. In another embodiment said anti-canceror cytotoxic agent is selected from the group consisting of linomide;inhibitors of integrin αvβ3 function; angiostatin; razoxin; tamoxifen;toremifen; raloxifene; droloxifene; iodoxyfene; megestrol acetate;anastrozole; letrazole; borazole; exemestane; flutamide; nilutamide;bicalutamide; cyproterone acetate; gosereline acetate; luprolide;finasteride; metalloproteinase inhibitors; inhibitors of urokinaseplasminogen activator receptor function; growth factor antibodies;growth factor receptor antibodies such as Avastin® and Erbitux®;tyrosine kinase inhibitors; serine/threonine kinase inhibitors);methotrexate; 5-fluorouracil; purine; adenosine analogues; cytosinearabinoside; doxorubicin; daunomycin; epirubicin; idarubicin;mitomycin-C; dactinomycin; mithramycin); cisplatin; carboplatin;nitrogen mustard; melphalan; chlorambucil; busulphan; cyclophosphamide;ifosfamide nitrosoureas; thiotephan; vincristine; Taxol®; Taxotere®;epothilone analogs; discodermolide analogs; eleutherobin analogs;etoposide; teniposide; amsacrine; topotecan; and flavopyridols.

In the field of medical oncology it is normal practice to use acombination of different forms of treatment to treat each patient withcancer. In medical oncology the other component(s) of such conjointtreatment in addition to the antiproliferative, antiangiogenic and/orvascular permeability reducing treatment defined herein before may be:surgery, radiotherapy or chemotherapy. Such chemotherapy may cover threemain categories of therapeutic agent:

1: antiangiogenic agents such as inhibitors of VEGF or related kinases(such as FLT, or KDR), linomide, antibodies which block angiogenesis,inhibitors of integrin αvβ3 function, angiostatin, razoxin;

2: cytostatic agents such as antiestrogens (for example tamoxifen,toremifen, raloxifene, droloxifene, iodoxyfene), progestogens (forexample megestrol acetate), aromatase inhibitors (for exampleanastrozole, letrazole, borazole, exemestane), antiharmones,antiprogestogens, antiandrogens (for example flutamide, nilutamide,bicalutamide, cyproterone acetate), LHRH agonists and antagonists (forexample gosereline acetate, luprolide), inhibitors of testosterone5α-dihydroreductase (for example finasteride), farnesyltransferaseinhibitors, anti-invasion agents (for example metalloproteinaseinhibitors like marimastat and inhibitors of urokinase plasminogenactivator receptor function) and inhibitors of growth factor function,(such growth factors include for example EGF, FGF, platelet derivedgrowth factor and hepatocyte growth factor such inhibitors includegrowth factor antibodies, growth factor receptor antibodies such asAvastin® and Erbitux®, tyrosine kinase inhibitors and serine/threoninekinase inhibitors);

3: antiproliferative/antineoplastic drugs and combinations thereof, asused in medical oncology, such as antimetabolites (for exampleantifolates like methotrexate, fluoropyrimidines like 5-fluorouracil,purine and adenosine analogues, cytosine arabinoside); Intercalatingantitumour antibiotics (for example anthracyclines like doxorubicin,daunomycin, epirubicin and idarubicin, mitomycin-C, dactinomycin,mithramycin); platinum derivatives (for example cisplatin, carboplatin);alkylating agents (for example nitrogen mustard, melphalan,chlorambucil, busulphan, cyclophosphamide, ifosfamide nitrosoureas,thiotephan); antimitotic agents (for example vinca alkaloids likevincristine and taxoids like Taxol®, Taxotere® and newer microbtubuleagents such as epothilone analogs, discodermolide analogs, andeleutherobin analogs); topoisomerase inhibitors (for exampleepipodophyllotoxins like etoposide and teniposide, amsacrine,topotecan); cell cycle inhibitors (for example flavopyridols).

Herein are provided methods for treating such conditions, comprisingadministering to a subject in need thereof an effective amount of atleast one compound of formula I or a salt thereof. Other therapeuticagents such as those described herein may be employed in combinationwith compounds of formula I. In the methods of the present invention,such other therapeutic agent(s) may be administered prior to,simultaneously with, or following administration of the inventivecompound(s).

When the terms “IKK associated condition” or “IKK associated disease ordisorder” are used herein, each is intended to encompass all of theconditions identified above as if repeated at length, as well as anyother condition that is modulated by IKK kinase activity.

The disclosure provides methods for treating such conditions, comprisingadministering to a subject in need thereof an effective amount of atleast one compound of Formula (I), or a pharmaceutically-acceptablesalt, hydrate, or prodrug thereof. The methods of treating IKKkinase-associated conditions may comprise administering compounds ofFormula (I) alone or in combination with each other and/or othersuitable therapeutic agents such as anti-inflammatory drugs,antibiotics, anti-viral agents, anti-oxidants, cholesterol/lipidlowering agents, anti-tumor agents including antiproliferative agents,and agents used to treat ischemia.

Examples of suitable other anti-inflammatory agents with which theinventive compounds may be used include aspirin, cromolyn, nedocromil,theophylline, zileuton, zafirlukast, monteleukast, pranleukast,indomethacin, and lipoxygenase inhibitors; non-steroidalantiinflammatory drugs (NSAIDs) (such as ibuprofen and naproxin); TNF-αinhibitors (such as tenidap and rapamycin or derivatives thereof), orTNF-α antagonists (e.g., infliximab, enbrel, D2E7, OR1384), cytokinemodulators (e.g. TNF-alpha converting enzyme [TACE] inhibitors,Interleukin-1 converting enzyme (ICE) inhibitors, Interleukin-1 receptorantagonists), prednisone, dexamethasone, Enbrel®, cyclooxygenaseinhibitors (i.e., COX-1 and/or COX-2 inhibitors such as Naproxen®,Celebrex®, or Vioxx®), CTLA4-Ig agonists/antagonists (LEA29Y), CD40ligand antagonists, IMPDH inhibitors (such as mycophenolate [CellCept®]and VX-497), integrin antagonists, alpha-4 beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, ICAM-1,prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493,CD4 antagonists (e.g., priliximab), other p38 mitogen-activated proteinkinase inhibitors, protein tyrosine kinase (PTK) inhibitors, therapiesfor the treatment of irritable bowel syndrome (e.g., Zelmac®, Zelnorm®,and Maxi-K® openers such as those disclosed in U.S. Pat. No. 6,184,231B1), corticosteroids (such as beclomethasone, triamcinolone, budesonide,fluticasone, flunisolide, dexamethasone, prednisone, and dexamethasone);disassociated steroids; chemokine receptor modulators (including CCR1,CCR2, CCR3, CCR4, and CXCR2 receptor antagonists); secretory andcytosolic phospholipase A2 inhibitors, VLA4 antagonists,glucocorticoids, salicylates, nitric oxide, and otherimmunosuppressants; and nuclear translocation inhibitors, such asdeoxyspergualin (DSG).

To treat pain, the inventive compounds may be used in combination withaspirin, NSAIDs, or with 5-HT 1 receptor agonists such as buspirone,sumitriptan, eletriptan or rizatriptan, or with opioids (e.g. morphine,codeine, hydomorphone).

Examples of suitable diabetic agents with which the inventive compoundsmay be used include insulin (of porcine or recombinant human originincluding, short acting insulins such as Humalog®, Regular, intermediateacting insulins such NPH, lente, and long acting insulins such asultralente or glarginine (Lantus®)); sulfonylureas such as glyburide andglipizide; secretegogues such as repaginide, and nateglinide; Peroisomeproliferators-activated receptor (PPAR) agonists such as rosiglitazoleand pioglitazone, and mixed PPAR alpha/gamma dual agonists agonists suchas muriglitazar; biquanides such as metformin, and glucosidaseinhibitors such as acarbose and miglitol, PPAR-alpha agonists, SGLT2inhibitors, inhibitors of fatty acid binding protein (aP2) such as thosedisclosed in U.S. Ser. No. 09/519,079 filed Mar. 6, 2000 and assigned tothe present assignee, glucagon-like peptide-1 (GLP-1), glucagonphosphorylase, and dipeptidyl peptidase IV (DP4) inhibitors.

Examples of suitable antibiotics with which the inventive compounds maybe used include β-lactams (e.g., penicillins, cephalosporins andcarbopenams); β-lactam and lactamase inhibitors (e.g., augamentin);aminoglycosides (e.g., tobramycin and streptomycin); macrolides (e.g.,erythromycin and azithromycin); quinolones (e.g., cipro and tequin);peptides and deptopeptides (e.g. vancomycin, synercid and daptomycin)metabolite-based anti-biotics (e.g., sulfonamides and trimethoprim);polyring systems (e.g., tetracyclins and rifampins); protein synthesisinhibitors (e.g., zyvox, chlorophenicol, clindamycin, etc.); andnitro-class antibiotics (e.g., nitrofurans and nitroimidazoles).

Examples of suitable antiviral agents for use with the inventivecompounds include nucleoside-based inhibitors, protease-basedinhibitors, and viral-assembly inhibitors.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate,risedronate, PTH, PTH fragment, raloxifene, calcitonin, RANK ligandantagonists, calcium sensing receptor antagonists, TRAP inhibitors,selective estrogen receptor modulators (SERM) and AP-1 inhibitors.

Examples of suitable anti-oxidants for use in combination with thecompounds of the present invention include lipid peroxidation inhibitorssuch as probucol, BO-653, Vitamin A, Vitamin E, AGI-1067, and α-lipoicacid.

A further use of the compounds of this invention is in combination withsteriodal or non-steroidal progesterone receptor agonists (“PRA”), suchas levonorgestrel, medroxyprogesterone acetate (MPA).

In addition, the compounds may be used with agents that increase thelevels of cAMP or cGMP in cells for a therapeutic benefit. For example,the compounds of the invention may have advantageous effects when usedin combination with phosphodiesterase inhibitors, including PDE1inhibitors (such as those described in Journal of Medicinal Chemistry,Vol. 40, pp. 2196-2210 [1997]), PDE2 inhibitors, PDE3 inhibitors (suchas revizinone, pimobendan, or olprinone), PDE4 inhibitors (such asrolipram, cilomilast, or piclamilast), PDE7 inhibitors, or other PDEinhibitors such as dipyridamole, cilostazol, sildenafil, denbutyline,theophylline (1,2-dimethylxanthine), ARIFLO™ (i.e.,cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid), arofyline, roflumilast, C-11294A, CDC-801, BAY-19-8004,cipamfylline, SCH351591, YM-976, PD-189659, mesiopram, pumafentrine,CDC-998, IC-485, and KW-4490.

The compounds may also be useful in combination with anticancerstrategies and chemotherapies such as taxol and/or cisplatin. Thecompounds may be used in conjunction with antitumor agents such aspaclitaxel, adriamycin, epithilones, cisplatin, and carboplatin.

In view of their usefulness in treating ischemia, the inventivecompounds may be used in combination with agents for inhibitingF₁F₀-ATPase, including efrapeptin, oligomycin, autovertin B, azide, andcompounds described in U.S. patent application Ser. No. 60/339,108,filed Dec. 10, 2001 and assigned to the present assignee; -alpha- orbeta-adrenergic blockers (such as propranolol, nadolol, carvedilol, andprazosin), or -β-adrenergic agonists (such as albuterol, terbutaline,formoterol, salmeterol, bitolterol, pilbuterol, and fenoterol);antianginal agents such as nitrates, for example, sodium nitrates,nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, andnitrovasodilators; antiarrhythmic agents including Class I agents (suchas propafenone); Class II agents (propranolol); Class III agents (suchas sotalol, dofetilide, amiodarone, azimilide and ibutilide); Class IVagents (such as ditiazem and verapamil); K⁺ channel modulators such asI_(Ach) inhibitors and inhibitors of the K_(v)1 subfamily of K⁺ channelopeners such as I_(Kur) inhibitors (e.g., compounds disclosed in U.S.application Ser. No. 09/729,731, filed Dec. 5, 2000); and gap-junctionmodulators such as connexions; anticoagulant or antithrombotic agentsincluding aspirin, warfarin, ximelagtran, low molecular weight heparins(such as lovenox, enoxaparain, and dalteparin), anti-platelet agentssuch as GPIIb/GPIIIa blockers, (e.g., abciximab, eptifibatide, andtirofiban), thromboxane receptor antagonists (e.g., ifetroban), P2Y₁ andP2Y₁₂ antagonists (e.g., clopidogrel, ticlopidine, CS-747, andaspirin/clopidogrel combinations), and Factor Xa inhibitors (e.g.,fondaprinux); and diuretics such as sodium-hydrogen exchange inhibitors,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, and amiloride.

Additionally, the compounds may be used in combination with lipidprofile modulators and antiatherosclerotic agents including HMG-CoAreductase inhibitors (e.g., pravastatin, simvastatin, atorvastatin,fluvastatin, cerivastatin, AZ4522, itavastatin [Nissan/Kowa]), ZD-4522(a.k.a. rosuvastatin, atavastatin or visastatin), pravachol, squalenesynthetase inhibitors, fibrates, bile acid sequestrants (such asquestran), niacin and niacin/statin combinations, lipooxygenaseinhibitors, ileal Na⁺/bile acid cotransporter inhibitors, ACAT1inhibitors, ACAT2 inhibitors, dual ACAT1/2 inhibitors, microsomaltriglyceride transport protein inhibitors (such as disclosed in U.S.Pat. Nos. 5,739,135, 5,712,279 and 5,760,246), cholesterol absorptioninhibitors (such as Zetia®), cholesterol ester transfer proteininhibitors (e.g., CP-529414), PPAR-delta agonists, PPAR-alpha agonists,dual PPAR-alpha/delta agonists, LXR-alpha agonists, LXR-beta agonists,LXR dual alpha/beta agonists, and SCAP modulators.

The combination of the compounds with other therapeutic agents may proveto have additive and synergistic effects. The combination may beadvantageous to increase the efficacy of the administration or decreasethe dosage to reduce possible side-effects.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art. In the methodsof the present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with, or following theadministration of the inventive compounds.

The disclosure also provides pharmaceutical compositions capable oftreating p38-kinase associated conditions, including TNF-α, IL-1, and/orIL-8 mediated conditions, as described above. The compositions maycontain other therapeutic agents as described above. Pharmaceuticalcompositions may be formulated by employing conventional solid or liquidvehicles or diluents, as well as pharmaceutical additives of a typeappropriate to the mode of desired administration (e.g., excipients,binders, preservatives, stabilizers, flavors, etc.) according totechniques such as those well known in the art of pharmaceuticalformulations.

The compounds of Formula (I) may be administered by any means suitablefor the condition to be treated, which may depend on the need forsite-specific treatment or quantity of drug to be delivered. Topicaladministration is generally preferred for skin-related diseases, andsystematic treatment preferred for cancerous or pre-cancerousconditions, although other modes of delivery are contemplated. Forexample, the compounds may be delivered orally, such as in the form oftablets, capsules, granules, powders, or liquid formulations includingsyrups; topically, such as in the form of solutions, suspensions, gelsor ointments; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular or intrasternal injection orinfusion techniques (e.g., as sterile injectable aq. or non-aq.solutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; rectally such asin the form of suppositories; or liposomally. Dosage unit formulationscontaining non-toxic, pharmaceutically acceptable vehicles or diluentsmay be administered. The compounds may be administered in a formsuitable for immediate release or extended release. Immediate release orextended release may be achieved with suitable pharmaceuticalcompositions or, particularly in the case of extended release, withdevices such as subcutaneous implants or osmotic pumps.

Exemplary compositions for topical administration include a topicalcarrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The inventive compounds may also be orally delivered bysublingual and/or buccal administration, e.g., with molded, compressed,or freeze-dried tablets. Exemplary compositions may includefast-dissolving diluents such as mannitol, lactose, sucrose, and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG); an excipient to aid mucosal adhesion such as hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodiumcarboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g.,GANTREZ®); and agents to control release such as polyacrylic copolymer(e.g., CARBOPOL 934®. Lubricants, glidants, flavors, coloring agents andstabilizers may also be added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions which may contain, for example, benzyl alcohol orother suitable preservatives, absorption promoters to enhance absorptionand/or bioavailability, and/or other solubilizing or dispersing agentssuch as those known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitablenon-toxic, parenterally acceptable diluents or solvents, such asmannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodiumchloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, suitable non-irritating excipients, suchas cocoa butter, synthetic glyceride esters or polyethylene glycols,which are solid at ordinary temperatures but liquefy and/or dissolve inthe rectal cavity to release the drug.

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for a mammal of from about 0.05 to 100 mg/kg of bodyweight of active compound per day, which may be administered in a singledose or in the form of individual divided doses, such as from 1 to 4times per day. Alternatively, the compound may be administered 1 or 2times per day. In another embodiment, the total amount administered perday is less than about 500 mg, alternatively about 100-350 mg, oralternatively, about 130-350 mg per day in either a once a day dose orin a twice a day dose. It will be understood that the specific doselevel and frequency of dosage for any particular subject may be variedand will depend upon a variety of factors, including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats, horses, and the like. Thus, when the term “patient” is usedherein, this term is intended to include all subjects, most preferablymammalian species, that are affected by mediation of IKK enzymeactivity.

At least one or more of the compounds described herein have been testedand have shown activity as inhibitors of IKK, IkB, NF-κB and/or TNF-α.For example, THP-1 (human monocytic cell line) obtained from ATCC wascultured in RPMI-1640 supplemented with 10% FBS, sodium pyruvate, HEPES,5-mercaptoethanol, Penicillin/Streptomycin. To a 96-well platecontaining THP-1 cells (1.4×10⁶/mL, 2.5×10⁵ cells/well) in 180 μLRPMI-1640 was added 10 μL of the test compound in 10% DMSO. Typically,test compound concentrations of 0.1-100 μM were used in the assay. Afterone hour at 37° C., 10 μL of 1000 ng/mL lipopolysaccharide (LPS fromSalmonella typhosa, Sigma) was added to each well. After an additional 6hours at 37° C., the supernatants were collected following a 5 minutecentrifugation of the plate to pellet the cells. The amount of TNFα inthese supernatants was then measured using a TNFα-specific ELISA(Pharmingen). After subtracting out the amount of TNFα in a control thathad not been treated with LPS, the percent inhibition was calculatedversus a control that was treated with LPS but with no test compoundadded. The compounds of this invention are active in vivo in theLPS-induced TNFα secretion model. Likewise, assays known in the fieldare applied to establish the activity of the compounds as inhibitors ofIKK, IkB, and/or the NF-κB pathway.

TNFα Secretion Assay

The ability of compounds to inhibit the production and secretion of TNFαfrom leukocytes was performed using either PBMC (obtained as describedabove) or the THP-1 cell line as a source of monocytes. Compounds werediluted in RPMI 1640 supplemented with 10% FBS and DMSO at a finalconcentration of 0.2%. Cells (2×105/well in U-bottom 96 well plates)were pre-incubated with compounds for 30 min at 37 C prior to additionof lipopolysaccharide (LPS) at a final concentration of 6.25 ng/ml in atotal volume of 200 μL. After 4 h at 37° C., 50 μL of supernatant wascarefully aspirated for detection of soluble TNFα. Soluble TNFα wasdetected by ELISA developed by R&D Systems (Minneapolis, Minn.)according to the manufacturer's instructions.

1. A compound of formula (I),

and salts thereof wherein R¹ is selected from hydrogen, C₁₋₃ alkyl, C₂₋₃alkenyl, and C₂₋₃ alkynyl; R² is selected from hydrogen, halo, alkyl,alkenyl, alkynyl, and perfluoroalkyl; R⁵ is selected from a) hydrogenand halo, (b) alkyl, alkenyl, alkynyl, and haloalkyl, any of which maybe optionally independently substituted as valence allows with one ormore Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ; (c) —OR¹¹, —SR¹¹ and —NR³R⁴; R³ andR⁴ are independently selected from (a) hydrogen, (b) alkyl, alkenyl,alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any ofwhich may be optionally independently substituted as valence allows withone or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ; (c) —OR¹¹, —NR¹²R¹³,—N(R¹²)C(O)R¹⁴, —N(R¹²)C(O)OR¹⁴, —N(R¹²)SO₂R¹⁴, —N(R¹²)C(O)NR¹² ^(a)R¹³, —N(R¹²)SO₂NR¹² ^(a) R¹³, —C(O)NR¹²R¹³, —SO₂R¹⁴, or —SO₂NR¹²R¹³; (d)R³ and R⁴ together with the nitrogen atom to which they are attachedcombine to form a 3 to 8 membered heterocyclic ring optionallyindependently substituted as valence allows with one or more Z¹ ^(b) ,Z² ^(b) and Z³ ^(b) ; R⁶ is (a) alkyl, alkenyl, alkynyl, any of which issubstituted with one or more as valence allows Z^(1f); cycloalkyl,heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl,(aryl)alkyl, or (heteroaryl)alkyl any of which may be optionallyindependently substituted as valence allows with one or more Z¹ ^(d) ,Z² ^(d) and Z³ ^(d) ; or (b) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) ,C(O)R⁷ ^(a) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ; R⁷ is (a)hydrogen, halo, or cyano, or (b) alkyl, alkenyl, alkynyl, haloalkyl,cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(heterocyclo)alkyl, (aryl)alkyl, or (heteroaryl)alkyl any of which maybe optionally independently substituted as valence allows with one ormore Z¹ ^(c) , Z² ^(c) and Z³ ^(c) ; R⁷ ^(a) is independently (a)hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, or (heteroaryl)alkyl any of which may be optionallyindependently substituted as valence allows with one or more Z¹ ^(c) ,Z² ^(c) and Z³ ^(c) ; R⁸ is (c) hydrogen, (d) alkyl, alkenyl, alkynyl,haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any ofwhich may be optionally independently substituted as valence allows withone or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or (c) —SO₂R¹⁰, —SO₂NR⁸ ^(b)R⁹ ^(b) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ; R⁸ ^(a) , R⁸ ^(b) ,R⁹ ^(a) and R⁹ ^(b) are independently (a) hydrogen, (b) alkyl, alkenyl,alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any ofwhich may be optionally independently substituted as valence allows withone or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; (c) R^(8a) and R^(9a)together with the nitrogen atom to which they are attached combine toform a 3 to 8 membered heterocyclic ring optionally independentlysubstituted as valence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³^(b) ; or (d) R^(8b) and R^(9b) together with the nitrogen atom to whichthey are attached combine to form a 3 to 8 membered heterocyclic ringoptionally independently substituted as valence allows with one or moreZ¹ ^(b) , Z² ^(b) and Z^(3b); R¹⁰, at each occurance, is independentlyalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(d) , Z² ^(d) and Z³^(d) ; R¹¹, R¹², R¹² ^(a) and R¹³ are independently (a) hydrogen, or (b)alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(e) , Z² ^(e) and Z³^(e) ; R¹⁴ is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, or (heteroaryl)alkyl any of which may be optionallyindependently substituted as valence allows with one or more Z¹ ^(e) ,Z² ^(e) and Z³ ^(e) ; Z¹ ^(a-) ¹ ^(e) , Z² ^(a-) ² ^(e) , and Z³ ^(a-) ³^(e) are optional substituents at each occurrence independently selectedfrom —W¹—V¹; —W²—V²; —W³—V³; —W⁴—V⁴; —W⁵—V⁵; where W¹⁻⁵ areindependently (1) a bond (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, or (heteroaryl)alkyl, any of which may be optionallyindependently substituted as valence allows with one or more V¹⁻⁵; orwhere V¹⁻⁵ are independently (1) H (2) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of which maybe optionally independently substituted as valence allows with one ormore of groups (3)-(28) of V¹⁻⁵; (3) —U¹—OY⁵, (4) —U¹—S—Y⁵, (5)—U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2, (6) —U¹—SO₃—H, or—U¹—S(O)_(t)Y⁵, (7) —U¹-halo, (8) —U¹-cyano, (9) —U¹-nitro, (10)—U¹—NY²Y³, (11) —U¹—N(Y⁴)—C(O)—Y¹, (12) —U¹—N(Y⁴)—C(S)—Y¹, (13)—U¹—N(Y⁴)—C(O)—NY²Y³, (14) —U¹—N(Y⁴)—C(O)—C(O)—NY²Y³, (15)—U¹—N(Y⁴)—C(O)—C(O)—OY⁵, (16) —U¹—N(Y⁴)—C(S)—NY²Y³, (17)—U¹—N(Y⁴)—C(O)O—Y⁵, (18) —U¹—N(Y⁴)—S(O)₂—Y¹, (19) —U¹—N(Y⁴)—S(O)₂—NY²Y³,(20) —U¹—C(O)—NY²Y³, (21) —U¹—OC(O)—NY²Y³, (22) —U¹—OC(O)—OY⁵, (23)—U¹—S(O)₂—N(Y⁴)—Y¹, (24) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, (25)—U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹, (26) —U¹—C(═NV¹ ^(a) )—NY²Y³, (27) oxo; (28)—U¹—Y⁵; Z^(1f), at each occurrence, is independently selected from (1)cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl, optionally substituted as valence allows with one ormore of groups (2) to (25) of Z^(1f); (2) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (3) —U¹—O—Y⁵, (4)—U¹—S—Y⁵, (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2, (6)—U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵, (7) —U¹-halo, (8) —U¹-cyano, (9)—U¹-nitro, (10) —U¹—NY²Y³, (11) —U¹—N(Y⁴)—C(O)—Y¹, (12)—U¹—N(Y⁴)—C(S)—Y¹, (13) —U¹—N(Y⁴)—C(O)—NY²Y³, (14) —U¹—N(Y⁴)—C(S)—NY²Y³,(15) —U¹—N(Y⁴)—C(O)O—Y⁵, (16) —U¹—N(Y⁴)—S(O)₂—Y¹, (17)—U¹—N(Y⁴)—S(O)₂—NY²Y³, (18) —U¹—C(O)—NY²Y³, (19) —U¹—OC(O)—NY²Y³ (20)—U¹—S(O)₂—N(Y⁴)—Y¹, (21) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, (22)—U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹, (23) —U¹—C(═NV¹ ^(a) )—NY²Y³, (24) oxo; (25)—U¹—Y⁵; V^(1a) is independently hydrogen, alkyl, —CN, —C(O)Y¹, —S(O)₂Y⁵,—C(O)NY²Y³, S(O)₂NY²Y³; Y¹, Y², Y³, Y⁴ and Y⁵ (1) are each independentlyhydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl, or(heteroaryl)alkyl, any of which may be optionally independentlysubstituted as valence allows with one or more Z⁴, Z⁵ and Z⁶; or (2) Y²and Y³ together with the nitrogen atom to which they are attachedcombine to form a 3 to 8 membered heterocyclic ring optionallyindependently substituted as valence allows with one or more Z⁴, Z⁵ andZ⁶, or (4) Y² and Y³ together with the nitrogen atom to which they areattached may combine to form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷ are eachindependently H or alkyl; and Z⁴, Z⁵, and Z⁶ are optional substituentsat each occurrence independently selected from (1) H (2) alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (3)—U¹—O—Y^(5a), (4) —U¹—S—Y^(5a), (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y^(5a)where t is 1 or 2, (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y^(5a), (7) —U¹-halo,(8) —U¹-cyano, (9) —U¹-nitro, (10) —U¹—NY² ^(a) Y³ ^(a) , (11) —U¹—N(Y⁴^(a) )—C(O)—Y^(1a), (12) —U¹—N(Y⁴ ^(a) )—C(S)—Y^(1a), (13) —U¹—N(Y⁴ ^(a))—C(O)—NY² ^(a) Y³ ^(a) , (14) —U¹—N(Y⁴ ^(a) )—C(S)—NY² ^(a) Y³ ^(a) ,(15) —U¹—N(Y⁴ ^(a) )—C(O)O—Y^(5a), (16) —U¹—N(Y⁴ ^(a) )—S(O)₂—Y^(1a),(17) —U¹—N(Y⁴ ^(a) )—S(O)₂—NY² ^(a) Y³ ^(a) , (18) —U¹—C(O)—NY² ^(a) Y³^(a) , (19) —U¹—OC(O)—NY² ^(a) Y³ ^(a) (20) —U¹—S(O)₂—N(Y⁴ ^(a))—Y^(1a), (21) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—NY² ^(a) Y³ ^(a) , (22)—U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—Y^(1a), (23) —U¹—C(═NV¹ ^(b) )—NY² ^(a)Y^(3a), (24) oxo; (25) —U¹—Y^(5a); V^(1b) is independently hydrogen,alkyl, —CN, —C(O)Y^(1a), —S(O)₂Y^(5a), S(O)₂NY^(2a)Y^(3a); Y¹ ^(a) , Y²^(a) , Y³ ^(a) , Y⁴ ^(a) and Y^(5a) (1) are each independently hydrogen,alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; U¹ isindependently (1) a single bond, (2) alkylene, (3) alkenylene, or (4)alkynylene.
 2. A compound of claim 1 wherein R¹ is selected fromhydrogen, C₁₋₃ alkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl; R² is selectedfrom hydrogen, alkyl, alkenyl, alkynyl, and haloalkyl; R⁵ is selectedfrom a) hydrogen and halo, (b) alkyl, alkenyl, alkynyl, and haloalkyl,any of which may be optionally independently substituted as valenceallows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ; (c) —OR¹¹, —SR¹¹and —NR³R⁴; R³ and R⁴ are independently selected from (a) hydrogen, (b)alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³^(b) ; (c) —OR¹¹, —NR¹²R¹³, —N(R¹²)C(O)R¹⁴, —N(R¹²)C(O)OR¹⁴,—N(R¹²)SO₂R¹⁴, —N(R¹²)C(O)NR¹² ^(a) R¹³, or —N(R¹²)SO₂NR¹² ^(a) R¹³ or—C(O)NR¹²R¹³, —SO₂R¹⁴, or —SO₂NR¹²R¹³; (d) R³ and R⁴ together with thenitrogen atom to which they are attached combine to form a 3 to 8membered heterocyclic ring optionally independently substituted asvalence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) ; R⁶ is(a) alkyl, alkenyl, alkynyl, any of which is substituted with one ormore as valence allows Z^(1f); cycloalkyl, heterocyclo, aryl,heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(d) , Z² ^(d) and Z³^(d) ; or (b) —SR^(7a), —SO₂R¹⁰, —SO₂NR⁸ ^(b) R⁹ ^(b) , C(O)R⁷ ^(a) ,—C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ; R⁷ is (a) hydrogen, halo, orcyano, (b) alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclo,aryl, heteroaryl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(c) , Z² ^(c) and Z³^(c) ; or (c), —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ; R⁷ ^(a) is areindependently (a) hydrogen, or (b) alkyl, alkenyl, alkynyl, haloalkyl,cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may beoptionally independently substituted as valence allows with one or moreZ¹ ^(c) , Z² ^(c) and Z³ ^(c) ; R⁸ is (e) hydrogen, (f) alkyl, alkenyl,alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any ofwhich may be optionally independently substituted as valence allows withone or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or (c) —SO₂R¹⁰, —SO₂NR⁸ ^(b)R⁹ ^(b) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) ; R⁸ ^(a) , R⁸ ^(b) ,R⁹ ^(a) and R⁹ ^(b) are independently (a) hydrogen, (b) alkyl, alkenyl,alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any ofwhich may be optionally independently substituted as valence allows withone or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; (c) R^(8a) and R^(9a)together with the nitrogen atom to which they are attached combine toform a 3 to 8 membered heterocyclic ring optionally independentlysubstituted as valence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³^(b) ; or (d) R^(8b) and R^(9b) together with the nitrogen atom to whichthey are attached combine to form a 3 to 8 membered heterocyclic ringoptionally independently substituted as valence allows with one or moreZ¹ ^(b) , Z² ^(b) and Z^(3b); R¹⁰, at each occurance, is independentlyalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(d) , Z² ^(d) and Z³^(d) ; R¹¹, R¹², R¹² ^(a) and R¹³ are independently (a) hydrogen, or (b)alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(e) , Z² ^(e) and Z³^(e) ; R¹⁴ is alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl,(cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, or (heteroaryl)alkyl any of which may be optionallyindependently substituted as valence allows with one or more Z¹ ^(e) ,Z² ^(e) and Z³ ^(e) ; Z¹ ^(a-) ¹ ^(e) , Z² ^(a-) ² ^(e) , and Z³ ^(a-) ³^(e) are optional substituents at each occurrence independently selectedfrom —W¹—V¹; —W²—V²; —W³—V³; —W⁴—V⁴; —W⁵—V⁵; where W¹⁻⁵ areindependently (1) a bond (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, or (heteroaryl)alkyl, any of which may be optionallyindependently substituted as valence allows with one or more V¹⁻⁵; orwhere V¹⁻⁵ are independently (1) H (2) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl, any of which maybe optionally independently substituted as valence allows with one ormore of groups (3)-(25) of V¹⁻⁵; (3) —U¹—O—Y⁵, (4) —U¹—S—Y⁵, (5)—U¹—(O)_(t)—H, —U¹—(O)_(t)—Y⁵ where t is 1 or 2, (6) —U¹—SO₃—H, or—U¹—S(O)_(t)Y⁵, (7) —U¹-halo, (8) —U¹-cyano, (9) —U¹-nitro, (10)—U¹—NY²Y³, (11) —U¹—N(Y⁴)—C(O)—Y¹, (12) —U¹—N(Y⁴)—C(S)—Y¹, (13)—U¹—N(Y⁴)—C(O)—NY²Y³, (14) —U¹—N(Y⁴)—C(S)—NY²Y³, (15)—U¹—N(Y⁴)—C(O)O—Y⁵, (16) —U¹—N(Y⁴)—S(O)₂—Y¹, (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,(18) —U¹—C(O)—NY²Y³, (19) —U¹—OC(O)—NY²Y³ (20) —U¹—S(O)₂—N(Y⁴)—Y¹, (21)—U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹, (23)—U¹—C(═NV¹ ^(a) )—NY²Y³, (24) oxo; (25) —U¹—Y⁵; Z^(1f), at eachoccurrence, is independently selected from (1) cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl,optionally substituted as valence allows with one or more of groups (2)to (25) of Z^(1f); (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl,alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl,heteroaryl, or (heteroaryl)alkyl; (3) —U¹—O—Y⁵, (4) —U¹—S—Y⁵, (5)—U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y⁵ where t is 1 or 2, (6) —U¹—SO₃—H, or—U¹—S(O)_(t)Y⁵, (7) —U¹-halo, (8) —U¹-cyano, (9) —U¹-nitro, (10)—U¹—NY²Y³, (11) —U¹—N(Y⁴)—C(O)—Y¹, (12) —U¹—N(Y⁴)—C(S)—Y¹, (13)—U¹—N(Y⁴)—C(O)—NY²Y³, (14) —U¹—N(Y⁴)—C(S)—NY²Y³, (15)—U¹—N(Y⁴)—C(O)O—Y⁵, (16) —U¹—N(Y⁴)—S(O)₂—Y¹, (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³,(18) —U¹—C(O)—NY²Y³, (19) —U¹—OC(O)—NY²Y³ (20) —U¹—S(O)₂—N(Y⁴)—Y¹, (21)—U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹, (23)—U¹—C(═NV¹ ^(a) )—NY²Y³, (24) oxo; (25) —U¹—Y⁵; V^(1a) is independentlyhydrogen, alkyl, —CN, —C(O)Y¹, —S(O)₂Y⁵, S(O)₂NY²Y³; Y¹, Y², Y³, Y⁴ andY⁵ (1) are each independently hydrogen, alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl, any of which maybe optionally independently substituted as valence allows with one ormore Z⁴, Z⁵ and Z⁶; or (2) Y² and Y³ may together be alkylene oralkenylene, completing a 3- to 8-membered saturated or unsaturated ringtogether with the atoms to which they are attached, or (4) Y² and Y³together with the nitrogen atom to which they are attached may combineto form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷ are each independently H oralkyl; and Z⁴, Z⁵, and Z⁶ are optional substituents at each occurrenceindependently selected from (1) H (2) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; (3) —U¹—O—Y^(5a),(4) —U¹—S—Y^(5a), (5) —U¹—C(O)_(t)—H, —U¹—C(O)_(t)—Y^(5a) where t is 1or 2, (6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y^(5a), (7) —U¹-halo, (8) —U¹-cyano,(9) —U¹-nitro, (10) —U¹—NY² ^(a) Y³ ^(a) , (11) —U¹—N(Y⁴ ^(a))—C(O)—Y^(1a), (12) —U¹—N(Y⁴ ^(a) )—C(S)—Y^(1a), (13) —U¹—N(Y⁴ ^(a))—C(O)—NY² ^(a) Y³ ^(a) , (14) —U¹—N(Y⁴ ^(a) )—C(S)—NY² ^(a) Y³ ^(a) ,(15) —U¹—N(Y⁴ ^(a) )—C(O)O—Y^(5a), (16) —U¹—N(Y⁴ ^(a) )—S(O)₂—Y^(1a),(17) —U¹—N(Y⁴ ^(a) )—S(O)₂—NY² ^(a) Y³ ^(a) , (18) —U¹—C(O)—NY² ^(a) Y³^(a) , (19) —U¹—OC(O)—NY² ^(a) Y³ ^(a) (20) —U¹—S(O)₂—N(Y⁴ ^(a))—Y^(1a), (21) —U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—NY² ^(a) Y³ ^(a) , (22)—U¹—N(Y⁴ ^(a) )—C(═NV¹ ^(b) )—Y^(1a), (23) —U¹—C(═NV¹ ^(b) )—NY² ^(a)Y^(3a), (24) oxo; (25) —U¹—Y⁵a; V^(1b) is independently hydrogen, alkyl,—CN, —C(O)Y^(1a), —S(O)₂Y^(5a), S(O)₂NY^(2a)Y^(3a); Y¹ ^(a) , Y² ^(a) ,Y³ ^(a) , Y⁴ ^(a) and Y^(5a) (1) are each independently hydrogen, alkyl,(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocylco)alkyl, heteroaryl, or (heteroaryl)alkyl; U¹ isindependently (1) a single bond, (2) alkylene, (3) alkenylene, or (4)alkynylene.
 3. A compound of claim 1 wherein R³ and R⁴ are independently(a) hydrogen, (b) alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,(cycloalkyl)alkyl, heterocyclo, (heterocyclo)alkyl, aryl, (aryl)alkyl,heteroaryl, or (heteroaryl)alkyl any of which may be optionallyindependently substituted as valence allows with one or more Z¹ ^(b) ,Z² ^(b) and Z³ ^(b) ; (c) —NR¹²R¹³; or (d) R³ and R⁴ together with thenitrogen atom to which they are attached combine to form a 3 to 8membered heterocyclic ring optionally independently substituted asvalence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³ ^(b) .
 4. Acompound of claim 3 wherein R⁶ is (a) alkyl, alkenyl, alkynyl, any ofwhich is substituted with one or more as valence allows Z^(1f); aryl,heteroaryl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo,(heterocyclo)alkyl, aryl, (aryl)alkyl, heteroaryl, or (heteroaryl)alkylany of which may be optionally independently substituted as valenceallows with one or more Z¹ ^(d) , Z² ^(d) and Z³ ^(d) ; or (b) —C(O)R⁷^(a) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .
 5. A compound of claim4 wherein R^(7a) is independently selected from (a) hydrogen, or (b)alkyl, haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any ofwhich may be optionally independently substituted as valence allows withone or more Z¹ ^(c) , Z² ^(c) and Z³ ^(c) .
 6. A compound of claim 5wherein R³ and R⁴ are independently hydrogen, alkyl, haloalkyl,(hydroxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl,(aryl)alkyl or (heteroaryl)alkyl and of which may be optionallyindependently substituted as valence allows with one or more Z¹ ^(b) ,Z² ^(b) and Z³ ^(b) ; —NR¹²R¹³; or alternatively, R³ and R⁴ togetherwith the nitrogen atom to which they are attached combine to form a 3 to6 membered heterocyclic ring selected from piperidinyl, morpholinyl,pyrrolidinyl, piperazinyl, and azetidinyl; optionally independentlysubstituted as valence allows with one or more Z¹ ^(b) , Z² ^(b) and Z³^(b) ; R⁶ is (a) alkyl, which is substituted with one or more as valenceallows Z^(1f); aryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl,heterocyclo, (heterocyclo)alkyl, aryl, (aryl)alkyl, heteroaryl, or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z¹ ^(d) , Z² ^(d) and Z³^(d) ; or (b) —C(O)R⁷ ^(a) , —C(O)OR⁷ ^(a) , or —C(O)NR⁸ ^(a) R⁹ ^(a) .7. A compound of claim 6 wherein R¹ is hydrogen, methyl, ethyl, propyl,i-propyl, prop-2-enyl, prop-1-enyl; and R² is hydrogen, methyl,trifluoromethyl, and phenyl.
 8. A compound of claim 1 wherein R¹ isselected from hydrogen and C₁₋₃ alkyl; R⁶ is (a) alkyl, alkenyl,alkynyl, any of which is substituted with one or more as valence allowsZ^(1f); cycloalkyl, heterocyclo, aryl, heteroaryl, (cycloalkyl)alkyl,(heterocyclo)alkyl, (aryl)alkyl, or (heteroaryl)alkyl any of which maybe optionally independently substituted as valence allows with one ormore Z^(1d), Z^(2d) and Z^(3d); or (b) —C(O)R^(7a), —C(O)OR^(7a), or—C(O)NR^(8a)R^(9a); Z^(1a-1e), Z^(2a-2e), and Z^(3a-3e) are optionalsubstituents at each occurrence independently selected from —W¹—V¹;—W²—V²; —W³—V³; —W⁴—V⁴; —W⁵—V⁵; where W¹⁻⁵ are independently (1) a bond(2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl; orwhere V¹⁻⁵ are independently (1) H (2) alkyl, (hydroxy)alkyl,(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,(heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any of which may beoptionally independently substituted as valence allows with one or moreof groups (3)-(28) of V¹⁻⁵; (3) —U¹—OY⁵, (4) —U¹—S—Y⁵, (5)—U¹—(O)_(t)—H, —U¹—(O)_(t)—Y⁵ where t is 1 or 2, (6) —U¹—SO₃—H, or—U¹—S(O)_(t)Y⁵, (7) —U¹-halo, (8) —U¹-cyano, (9) —U¹-nitro, (10)—U¹—NY²Y³, (11) —U¹—N(Y⁴)—C(O)—Y¹, (12) —U¹—N(Y⁴)—C(S)—Y¹, (13)—U¹—N(Y⁴)—C(O)—NY²Y³, (14) —U¹—N(Y⁴)—C(O)—C(O)—NY²Y³, (15)—U¹—N(Y⁴)—C(O)—C(O)—OY⁵, (16) —U¹—N(Y⁴)—C(S)—NY²Y³, (17)—U¹—N(Y⁴)—C(O)O—Y⁵, (18) —U¹—N(Y⁴)—S(O)₂—Y¹, (19) —U¹—N(Y⁴)—S(O)₂—NY²Y³,(20) —U¹—C(O)—NY²Y³, (21) —U¹—OC(O)—NY²Y³, (22) —U¹—OC(O)—OY⁵, (23)—U¹—S(O)₂—N(Y⁴)—Y¹, (24) —U¹—N(Y⁴)—C(═NV^(1a))—NY²Y³, (25)—U¹—N(Y⁴)—C(═NV^(1a))—Y¹, (26) —U¹—C(═NV^(1a))—NY²Y³, (27) oxo; (2528—U¹—Y⁵; Z¹ ^(f) , at each occurrence, is independently selected from (1)cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl, optionally substituted as valence allows with groups(2) to (25); (2) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl, or(heteroaryl)alkyl; (3) —U¹—O—Y⁵, (4) —U¹—S—Y⁵, (5) —U¹—C(O)_(t)—H,—U¹—C(O)_(t)—Y⁵ where t is 1 or 2, 6) —U¹—SO₃—H, or —U¹—S(O)_(t)Y⁵, (7)—U¹-halo, (8) —U¹-cyano, (9) —U¹-nitro, (10) —U¹—NY²Y³, (11)—U¹—N(Y⁴)—C(O)—Y¹, (12) —U¹—N(Y⁴)—C(S)—Y¹, (13) —U¹—N(Y⁴)—C(O)—NY²Y³,(14) —U¹—N(Y⁴)—C(S)—NY²Y³, (15) —U¹—N(Y⁴)—C(O)O—Y⁵, (16)—U¹—N(Y⁴)—S(O)₂—Y¹, (17) —U¹—N(Y⁴)—S(O)₂—NY²Y³, (18) —U¹—C(O)—NY²Y³,(19) —U¹—OC(O)—NY²Y³ (20) —U¹—S(O)₂—N(Y⁴)—Y¹, (21) —U¹—N(Y⁴)—C(═NV¹ ^(a))—NY²Y³, (22) —U¹—N(Y⁴)—C(═NV¹ ^(a) )—Y¹, (23) —U¹—C(═NV¹ ^(a) )—NY²Y³,(24) oxo; (25) —U¹—Y⁵; V^(1a) is independently hydrogen, alkyl, —CN,—C(O)Y¹, —C(O)NY²Y³, —S(O)₂Y⁵, S(O)₂NY²Y³; Y¹, Y², Y³, Y⁴ and Y⁵ (1) areeach independently hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl,alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl,heteroaryl, or (heteroaryl)alkyl, any of which may be optionallyindependently substituted as valence allows with one or more Z⁴, Z⁵ andZ⁶; or (2) Y² and Y³ together with the nitrogen atom to which they areattached combine to form a 3 to 8 membered heterocyclic ring optionallyindependently substituted as valence allows with one or more Z⁴, Z⁵ andZ⁶, or (4) Y² and Y³ together with the nitrogen atom to which they areattached may combine to form a group —N═CY⁶Y⁷ where Y⁶ and Y⁷ are eachindependently H or alkyl.
 9. A compound of claim 8 wherein R³ and R⁴ areindependently (a) hydrogen, (b) alkyl, haloalkyl, (hydroxy)alkyl,cycloalkyl, (cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or(heteroaryl)alkyl any of which may be optionally independentlysubstituted as valence allows with one or more Z^(1b), Z^(2b) andZ^(3b); (c) —NR¹²R¹³; or (d) R³ and R⁴ together with the nitrogen atomto which they are attached combine to form a 3 to 8 memberedheterocyclic ring optionally independently substituted as valence allowswith one or more Z^(1b), Z^(2b) and Z^(3b).
 10. A compound of claim 9wherein R⁶ is (a) alkyl, alkenyl, alkynyl any of which is substitutedwith one or more as valence allows Z^(1f); aryl, heteroaryl,(cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl, or (heteroaryl)alkylany of which may be optionally independently substituted as valenceallows with one or more Z^(1d), Z^(2d) and Z^(3d); or (b) —C(O)R^(7a),—C(O)OR^(7a), or —C(O)NR^(8a)R^(9a).
 11. A compound of claim 10 whereinR^(7a) is independently selected from (a) hydrogen, or (b) alkyl,haloalkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,heterocyclo, (heterocyclo)alkyl, heteroaryl, or (heteroaryl)alkyl any ofwhich may be optionally independently substituted as valence allows withone or more Z^(1c), Z^(2c) and Z^(3c).
 12. A compound of claim 11wherein Z^(1b), Z^(2b) and Z^(3b) are optional substituentsindependently selected from alkyl, heteroaryl, —OH, —O—Y⁵, —U¹—NY²Y³,—C(O)_(t)H, —C(O)_(t)Y⁵; Z^(1c) is (a) —OH, —OY⁵ or (b) aryl optionallysubstituted with —OH or —OY⁵; Z^(1d), Z^(2d) and Z^(3d) are optionalsubstituents independently selected from (a) cyano, halo, —OH, —OY⁵,—U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y¹, —U¹—C(O)—NY²Y³, —S(O)_(t)Y⁵; (b)alkyl or alkoxy optionally substituted with one or more cyano, halo,—OH, —OY⁵, —U¹—NY²Y³, —C(O)_(t)H, —C(O)_(t)Y¹, —U¹—C(O)—NY²Y³,—OC(O)—NY²Y³, OC(O)—OY⁵, —U¹—N(Y⁴)—C(O)—Y¹, —U¹—N(Y⁴)—C(O)—NY²Y³,—U¹—N(Y⁴)—C(O)O—Y⁵, —N(Y⁴)—S(O)₂—Y¹, —N(Y⁴)—C(O)—C(O)—NY²Y³,—N(Y⁴)—C(O)—C(O)—OY⁵, —U¹—N(Y⁴)—C(═NV¹ ^(a) )—NY²Y³, —U¹—N(Y⁴)—C(═NV¹^(a) )—Y¹, —S(O)_(t)Y, —U¹-heteroaryl, or U1-heterocyclo, whereinheteroaryl and heterocyclo are substituted as valence allows with one ormore of groups (3)-(28) of V¹⁻⁵.
 13. A compound of claim 12 wherein R³is hydrogen; R⁴ is alkyl, haloalkyl, (hydroxy)alkyl, cycloalkyl,(cycloalkyl)alkyl, (heterocyclo)alkyl, (aryl)alkyl or (heteroaryl)alkyland of which may be optionally independently substituted as valenceallows with one or more Z^(1b), Z^(2b) and Z^(3b); alternatively, R³ andR⁴ together with the nitrogen atom to which they are attached combine toform a 3 to 6 membered heterocyclic ring selected from piperidinyl,morpholinyl, pyrrolidinyl, and azetidinyl; optionally independentlysubstituted as valence allows with one or more Z^(1b), Z^(2b) andZ^(3b); R⁶ is (a) alkynyl optionally substituted with Z^(1d) whereZ^(1d) is aryl which may be further optionally independently substitutedwith one or more cyano, halo, —OH, —OY, —U¹—NY²Y³, —C(O)_(t)H,—C(O)_(t)Y, or, —S(O)_(t)Y; or (b) aryl optionally independentlysubstituted as valence allows with one or more Z^(1d), Z^(2d) andZ^(3d); (c) heteroaryl optionally independently substituted as valenceallows with one or more Z^(1d), Z^(2d) and Z^(3d); or (d) —C(O)OR⁷ ^(a), or —C(O)NR⁸ ^(a) R⁹ ^(a) ; where U¹ is a bond or alkylene.
 14. Acompound of claim 13 wherein R¹ is alkyl; and R² is hydrogen.
 15. Thecompound of clais 1, wherein R⁵ is selected from a) hydrogen, or (b)alkyl, alkenyl, alkynyl, and haloalkyl, any of which may be optionallyindependently substituted as valence allows with one or more Z¹ ^(b) ,Z² ^(b) and Z³ ^(b) ; R⁶ is

 which may be further substituted with with one or more Z¹ ^(d) , Z²^(d) and Z³ ^(d) .
 16. The compound of claim 1, wherein R⁵ is —NR³R⁴.17. A pharmaceutical composition comprising (a) at least one compoundaccording to claim 1, or a pharmaceutically acceptable salt, hydrate orprodrug thereof, and (b) a pharmaceutically-acceptable carrier ordiluent.
 18. The method of treating disorders comprising administeringto a mammal in need thereof a therapeutically-effective amount of atleast one compound according to claim 1 wherein the disorder is selectedfrom rheumatoid arthritis, asthma, inflammatory bowel disease, chronicobstructive pulmonary disease, and psoriasis.
 19. A method of treatingcancer comprising administering to a mammal in need thereof atherapeutically-effective amount of at least one compound according toclaims 1.